Indole derivatives thromboxane A2 antagonists

ABSTRACT

Compounds of formula (I): ##STR1## and pharmaceutically acceptable salt and biolabile esters thereof, wherein R 1  is H, C 1  -C 4  alkyl, phenyl optionally substituted by up to three substituents independently selected from C 1  -C 4  alkyl, C 1  -C 4  alkoxy, halogen and CF 3 , or is 1-imidazolyl, 3-pyridyl or 4-pyridyl; R 2  is H or C 1  -C 4  alkyl, R 3  is SO 2  R 4  or COR 4  where R 4  is C 1  -C 6  alkyl, C 1  -C 3  perfluoroalkyl(CH 2 ) p , C 3  -C 6  cycloalkyl(CH 2 ) p , aryl(CH 2 ) p , or heteroaryl(CH 2 ) p , p being 0, 1 or 2, or R 4  may be NR 5  R 6  where R 5  is H or C 1  -C 4  alkyl and R 6  is C 1  -C 6 , alkyl, C 3  -C 6  cycloalkyl or aryl, or R 5  and R 6  together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocyclic ring which may optionally incorporate a carbon-carbon double bond or a further heteroatom linkage selected from O, S, NH, N(C 1  -C 4  alkyl) and N(C 1  -C 5  alkanoyl); X is CH 2  or a direct link, with the proviso that when R 1  is 1-imidazolyl then X is CH 2  ; m is 2, or 3; n is 0, 1 or 2, and wherein the group (CH 2 ) n  NHR 3  is attached at the 5-position when n is 0 or 1, or at the 5- or 4-position when n is 2. These compounds are selective TXA 2  and PGH 2  antagonists. Some also inhibit thromboxane synthetase.

BACKGROUND OF THE INVENTION

This invention relates to certain indole alkanoic acids. Such compoundsare able to selectively antagonise the effect of thromboxane A₂ (TXA₂),and its precursor prostaglandin H₂ (PGH₂), at the thromboxane receptor.In addition, certain of the compounds also selectively inhibit thethromboxane synthetase enzyme. The compounds are thus useful astherapeutic agents and they may be used either alone, or, in the case ofcompounds which do not inhibit the thromboxane synthetase enzyme,preferably in combination with a thromboxane synthetase inhibitor, forexample in the treatment of atherosclerosis and unstable angina and forprevention of reocculsion, both acute and chronic, after percutaneoustransluminal coronary and femoral angioplasty. The compounds may alsofind clinical utility in a further variety of disease conditions inwhich thromboxane A₂ has been implicated such as in the treatment ofmyocardial infarction, stroke, cardiac arrhythmias, transient isohaemicattack, tumour metastasis, peripheral vascular disease, bronchialasthma, renal disease, cyclosporin-induced neprotoxicity, renalallograft rejection, vascular complications of diabetes and endotoxinshock, trauma, pre-eclampsia and in coronary artery bypass surgery andhaemodialysis.

SUMMARY OF THE INVENTION

The compounds of the invention are of formula (I): ##STR2## andpharmaceutically acceptable salts and biolabile esters thereof, whereinR¹ is H, C₁ -C₄ alkyl, phenyl optionally substituted by up to threesubstituents independently selected from C₁ -C₄ alkyl, C₁ -C₄ alkoxy,halogen and CF₃, or is 1-imidazolyl, 3-pyridyl or 4-pyridyl;

R² is H or C₁ -C₄ alkyl,

R³ is SO₂ R⁴ or COR⁴ where R⁴ is C₁ -C₆ alkyl, C₁ -C₃perfluoralkyl(CH₂)_(p), C₃ -C₆ cycloalkyl(CH₂)_(p), aryl(CH₂)_(p) orheteroaryl(CH₂)_(p), p being 0, 1 or 2, or R⁴ may be NR⁵ R⁶ where R⁵ isH or C₁ -C₄ alkyl and R⁶ is C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl or aryl, orR⁵ and R⁶ together with the nitrogen atom to which they are attachedform a 5- to 7-membered heterocyclic ring which may optionallyincorporate a carbon-carbon double bond or a further heteroatom linkageselected from O, S, NH, N(C₁ -C₄ alkyl) and N(C₁ -C₅ alkanoyl);

X is CH₂ or a direct link, with the proviso that when R¹ is 1-imidazolylthen X is CH₂ ;

m is 2, or 3;

n is 0, 1 or 2,

and wherein the group (CH₂)_(n) NHR³ is attached at the 5-position whenn is 0 or 1, or at the 5- or 4-position when n is 2.

In the above definitions "aryl" means phenyl or naphthyl and"heteroaryl" means furyl, thienyl or pyridyl, any of which ring systemsmay optionally be substituted with one to three substituents eachindependently chosen from C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo, CF₃, OCF₃and CN. Alkyl and alkoxy groups having three or more carbon atoms may bestraight chain or branched chain. "Halo" means fluoro, chloro, bromo oriodo.

Compounds containing asymmetric centres can exist as enantiomers anddiastereisomers, and the invention includes the separated individualisomers as well as mixtures of isomers.

Also included in the invention are radiolabelled derivatives ofcompounds of formula (I) which are suitable for biological studies.

The term biolabile ester in the above definition means apharmaceutically acceptable, biologically degradable ester derivative ofa compound of formula (I), that is a prodrug which, upon administrationto an animal or human being, is converted in the body to a compound offormula (I). In the case of the compounds of formula (I), such biolabileester prodrugs are particularly advantageous in providing compounds offormula (I) suitable for oral administration. The suitability of anyparticular ester-forming group can be assessed by conventional in vivoanimal or in vitro enzyme hydrolysis studies. Thus desirably, foroptimum effect, the ester should only be hydrolysed after absorption iscomplete. Accordingly, the ester should be resistant to prematurehydrolysis by digestive enzymes before absorption, but should beproductively hydrolysed by, for example, gut-wall, plasma or liverenzymes. In this way, the active acid is released into the bloodstreamfollowing oral absorption of the prodrug.

Suitable biolabile esters may include alkyl, alkanoyloxyalkyl,cycloalkanoyloxyalkyl aroyloxyalkyl and alkoxycarbonyloxyalkyl esters,including cycloalkyl and aryl substituted derivatives thereof, arylesters and cycloalkyl esters, wherein said alkyl, alkanoyl or alkoxygroups may contain from 1 to 8 carbon atoms and be branched-chain orstraight-chain, said cycloalkyl groups may contain from 3-7 carbon atomsand said cycloalkyl groups may contain from 3-7 carbon atoms whereinboth are optionally benzo-fused, and said aryl and aroyl groups includesubstituted phenyl, naphthyl or indanyl ring systems. Preferably, thebiolabile esters of the invention are C₁ -C₄ alkyl esters. Morepreferably, they are methyl, ethyl and t-butyl esters.

The pharmaceutically acceptable salts of the compounds of formula (I)are those formed with bases which provide non-toxic salts. Examplesinclude the alkali and alkaline earth metal salts such as the sodiumpotassium or calcium salts, and salts with amines such as diethylamine.

A preferred group of compounds of formula (I) is that where R¹ isoptionally substituted phenyl or pyridyl, R² is H, R³ is SO₂ R⁴ where R⁴is optionally substituted phenyl, X is CH₂, m is 2, n is 0 or 2, and(CH₂)_(n) NHR³ is attached at the 5-position.

Another preferred group of compounds of formula (I) is that where R¹ ispyridyl, R² is H, R³ is SO₂ R⁴ where R⁴ is optionally substituted phenylor, R³ is COR⁴ where R⁴ is alkyl, X is CH₂, m is 2, n is 2 and (CH₂)_(n)NHR³ is attached at the 4-position.

Particularly preferred are such compounds wherein R¹ is 4-fluorophenyl,R² is H, R³ is 4-arylsulphonyl, X is CH₂, m is 2, n is 0 and (CH₂)_(n)NHR³ is attached at the 5-position, or wherein R¹ is pyridyl, R² is H,R³ is 3-methylbutanoyl, X is CH₂, m is 2, n is 2 and (CH₂)_(n) NHR³ isattached at the 4-position.

DETAILED DESCRIPTION OF THE INVENTION

In another aspect the present invention provides processes for thepreparation of compounds of formula (I), their biolabile esters andpharmaceutically acceptable salts.

In one process, the compounds of formula (I) are obtained by hydrolysisof their lower alkyl ester precursors of formula (II): ##STR3## whereinR¹, R², R³, m, n, p and X are as defined for formula (I) and R⁷ is C₁-C₄ alkyl, preferably methyl, ethyl or t-butyl. The reaction can beconducted under basic or acidic conditions, e.g. with excess aqueousalkali, preferably sodium hydroxide solution, or excess hydrochloricacid respectively, optionally with a suitable co-solvent such as a C₁-C₄ alkanol, preferably methanol, at from ambient temperature to thereflux temperature of the reaction medium.

In the case where R¹ ═H and X═CH₂ (i.e. a 3-methylindole), the finalcompounds may be prepared by hydrogenolysis of the compound where R¹=1-imidazolyl and X═CH₂ . ##STR4##

The compounds of formula (II) where R³ is SO₂ R⁴ or COR⁴ may generallybe prepared by sulphonation/sulphamoylation or acylation, respectivelyof an amine of formula (III): ##STR5## where R¹, R², R⁷, m, n and X areas defined above. Sulphonylation may be carried out by reaction of theamine of formula (III) with a sulphonyl halide of formula R⁴ SO₂ Hal,where Hal is a halogen atom (preferably the chloride), or with asulphonic anhydride of formula (R⁴ SO₂)O, where R⁴ is as defined abovebut is other than NR⁵ R⁶. Sulphamoylation may be carried out similarlyby reaction of compound (III) with a sulphamoyl halide (preferably thechloride) of formula R⁵ R⁶ NSO₂ Hal, to yield a compound of formula (II)in which R⁴ is NR⁵ R⁶.

Acylation may be carried out by reaction of compound (III) with an acidanhydride of formula (R⁴ CO)₂ O or acid halide R⁴ CO Hal (preferably thechloride) where R⁴ is as defined above.

These reactions may be carried out in the presence of a base such astriethylamine, pyridine, 4-dimethylaminopyridine or combination thereofto act as an acid scavenger in a suitable solvent such as methylenechloride or tetrahydrofuran.

Alternatively, the acylation may be carried out by reaction of compound(III) with an imidazolide of formula ##STR6## generated in situ byreaction of an acid of formula R⁴ CO₂ H and carbonyldiimidazole in asolvent such as tetrahydrofuran, dimethylformamide or methylenechloride.

The novel compounds of formula (II) and (III) above are themselves partof the present invention.

The amines of formula (III) may be prepared by different methods,depending on the value of n. When n=2 the amine may be prepared by aminedeprotection from a corresponding carbamate of formula (IV): ##STR7##where R¹, R², R⁷, m and X are as defined above and R⁸ is a group whichcan be selectively removed in the presence of group R⁷ to give therequired amine. A suitable R⁸ group is benzyl, which may be removed bycatalytic transfer hydrogenation using ammonium formate and apalladium/carbon catalyst in a suitable solvent such as amethanol/tetrahydrofuran mixture at reflux temperature. Alternatively,this benzyl group may be removed by hydrogenation using hydrogen, at apressure of 1-5 atmospheres, in the presence of a palladium/carboncatalyst and a solvent such as tetrahydrofuran, methanol or ethanol at atemperature from ambient to 50° C. Another possible R⁸ is t-butyl, whichmay be removed by reaction with an acid such as hydrochloric ortrifluoroacetic acid in a solvent such as dichloromethane at atemperature from 0° to 20° C.

When n=1 the amine of formula (III) may be prepared by reduction of anitrile of formula (V): ##STR8## where R¹, R², R⁷, X and m are asdefined above. This reduction may be performed by hydrogenation in thepresence of a metal catalyst such as rhodium/alumina, preferably in thepresence of ammonia, or Raney nickel under the usual conditions for thisreaction. Reduction may also be carried out by means of diborane.

When n=0 the desired amines of formula (III) may be prepared byreduction of corresponding nitro compounds of formula (VI): ##STR9##where R¹, R², R⁷, m and X are as defined above. This reduction may beachieved by treatment with hydrogen, typically at a pressure of 1-5atmospheres, in a suitable solvent such as methanol or ethanol with acatalyst such as palladium/carbon at a temperature of up to 50° C.

The carbamates of formula (IV) may be prepared from carboxylic acids offormula (VII): ##STR10## where R¹, R², R⁷, X and m are as defined aboveby reaction with diphenylphosphoryl azide in a suitable solvent, such asdioxan, at reflux in the presence of Et₃ N to form an acyl azide whichundergoes the Curtius re-arrangement to give the correspondingisocyanate. Addition of an alcohol, such as benzyl or t-butyl alcohol,gives the corresponding carbamate (IV). Excess alcohol may be used asthe solvent in place of dioxan.

The acids of formula (VII) may themselves be prepared from acrylicesters of formula (VIII): ##STR11## where R¹, R², R⁷, m and X are asdefined above and R⁸ is a group such as benzyl or t-butyl. Catalytictransfer hydrogenation or conventional hydrogenation, as described abovein relation to compounds (IV), reduces the double bond of the acrylicsubstituent and, when R⁹ is benzyl, also removes the R⁹ group to yieldan acid of formula (VII). When R⁹ is a group not removed byhydrogenolysis, such as t-butyl, it may be removed by treatment with astrong acid, such as hydrochloric or trifluoroacetic acid, before orafter hydrogenation of the acrylic double bond.

The esters of formula (VIII), nitriles of formula (V) and nitrocompounds of formula (VI) may all be prepared from indole compounds offormula (IX): ##STR12## where R¹, R² and X are as defined above and R¹⁰is ##STR13## CN or NO₂, respectively. When m=2 compound (IX) may beallowed to react with compound ##STR14## in the presence of a basecatalyst to give compound (VIII), (V) or (VI) by Michael addition. Whenm=3 these compounds may be obtained by reaction of compound (IX) with anester of formula Hal-(CH₂)₃ --CO₂ R⁷, where Hal is chloro, bromo oriodo, in the presence of a base such as sodium hydride indimethylformamide as a solvent.

When R¹⁰ is the acrylic ester group ##STR15## compound (IX) may beobtained from a bromoindole of formula (X): ##STR16## where R¹, R² and Xare as defined above by a Heck reaction with an appropriate acrylicester in the presence of palladium (II) acetate, tri-o-tolylphosphineand a base such as triethylamine in a suitable solvent such asacetonitrile or dimethylformamide at a temperature from 80° to 160° C.

When R¹⁰ is CN compound (IX) may be prepared from compound (X) byreaction of the latter with a cyanide, such as CuCN in a solvent such asdimethylformamide, dimethylacetamide or N-methylpyrrolidone at refluxtemperature.

When indole intermediates in which X is CH₂, R² is C₁ -C₄ alkyl and R¹is not 1-imidazolyl are to be obtained, compounds (IX or X) in which Xis a direct link and R¹ is H, R² is C₁ -C₄ alkyl may be obtained by theabove-described methods and subsequently allowed to react with anappropriate aldehyde in the presence of trifluoroacetic acid andtriethylsilane: ##STR17##

When X is CH₂ and R¹ is a 1-imidazolyl group in the desired compound thefollowing synthesis may be used: ##STR18##

In this synthesis the starting compound in which R² is as defined aboveand R¹⁰ is ##STR19## or CN reacts with formaldehyde, dimethylamine andacetic acid to give the corresponding indole having a --CH₂ NMe₂substituent at the 3-position. Subsequent treatment with imidazole in asolvent such as toluene or xylene, at the boiling point of the solvent,results in replacement of the --NMe₂ group with a 1-imidazolyl group.

The bromo-indole intermediates of formula (X) may be prepared from knowncompounds by standard methods, such as the Fischer indole synthesis orby substitution of bromocompounds (X) in which X is a direct link and R¹is H. For example, a compound of formula (XI): ##STR20## where R² is asdefined above may be converted to a compound (X) where X is CH₂ byreaction with aldehyde R¹ CHO in the presence of trifluoroacetic acidand Et₃ SiH, or with a Grignard reagent MeMgHal where Hal is a halogenatom followed by reaction with halide R¹ CH₂ Cl or R¹ CH₂ Br.

The nitroindole intermediates (IX) in which R¹⁰ is NO₂ may be made byknown methods, such as the Fischer indole synthesis applied to theappropriate nitrophenylhydrazone. When X is CH₂ and R¹ is imidazolylthese intermediates may be prepared from those in which X is a directlink and R¹ is H by reaction with formaldehyde/dimethylamine/acetic acidfollowed by reaction with imidazole, as described above.

As previously mentioned, the compounds of the invention are able toantagonise the action of thromboxane A₂ and prostaglandin H₂ at thethromboxane A₂ receptor.

Thromboxane A₂ (TXA₂) is a naturally occurring prostanoid which is knownto be a potent vascoconstrictor and platelet aggregating agent. TXA₂ isalso believed to be involved in a number of disease states includingatherosclerosis, ischaemic heart disease, peripheral vascular diseaseand myocardial infarction. TXA₂ acts at the thromboxane A₂ receptor, atwhich site other prostanoids, notably prostaglandin H₂, may also beagonists.

TXA₂ synthetase inhibitors prevent formation of TXA₂ from the precursorPGH₂ which may be diverted to produce more of the vasodilator andantiaggregatory PGI₂. However, a possible drawback with this type ofagent is that accumulated PGH₂ substrate can activate the TXA ₂receptor, thus partly eliminating or negating the benefit of suppressingTXA₂ formation. Furthermore, if inhibition of TXA₂ synthetase isincomplete, sufficient TXA₂ may be available to induce some plateletactivation. Both of these drawbacks can be overcome if a TXA₂ receptorantagonist is present to block the action of any TXA₂ or accumulatedPGH₂ substrate. It has been demonstrated that combination of a TXA₂antagonist and a TXA₂ synthetase inhibitor produces a synergistic effecton platelet aggregation in vitro (Watts et al., Brit. J. Pharmacol.,102, 497, 1991). In addition, administration of the TXA₂ antagonistsulotroban and the TXA₂ synthetase inhibitor dazoxiben to humanvolunteers gave a stronger inhibition of platelet aggregation thaneither agent alone (Gresele et al.,). Clin. Invest., 80, 1435, 1987).

Thus the compounds of the invention are of particular value when used incombination with a selective inhibitor of the thromboxane synthetaseenzyme and the resulting combinations will find utility in the diseasestates already mentioned as well as those in which PGD₂ and PGF₂α may beimplicated as mediators, such as diabetes, bronchial asthma, and otherinflammatory conditions.

Thus the present invention also provides a pharmaceutical compositioncomprising as active ingredients a novel TXA₂ receptor antagonist of theformula (I) as hereinbefore defined and a TXA₂ synthetase inhibitor,together with a pharmaceutically acceptable diluent or carrier.

Suitable TXA₂ synthetase inhibitors for inclusion as active ingredientsin the composition according to the invention include, for example, theknown compounds:

1) 4- 2-(1H-imidazol-1-yl)ethoxy!benzoic acid, (dazoxiben, R. P.Dickinson, et al, J. Med. Chem., 1985, 28, 1427-1432);

2) 3-(1H-imidazol-1-ylmethyl)-2-methyl-1H-indole-1-propanoic acid,(dazmegrel, R. P. Dickinson, et al, J. Med. Chem., 1986, 29, 342-346);

3) 2-methyl-3-(3-pyridylmethyl)-1H-indole-1-propanoic acid, (Europeanpatent 0054417);

4) 3-methyl-2-(3-pyridylmethyl)benzo b!thiophene-5-carboxylic acid,(UK-49,883, P. E. Cross, R. P. Dickinson, Spec Publ. Royal Soc. Chem.No. 50, p. 268-285, 1984);

5) 1,3-dimethyl-2-(1H-imidazol-1-ylmethyl)-1H-indol-5-carboxylic acid,(R. P. Dickinson et al, J. Med. Chem., 1986, 29, 1643-1650);

6) a carboxy, lower alkoxycarbonyl or carbamoyl substitutedbenzothiophene, benzofuran or indole as claimed in European patent0073663, or the novel compound:

7) 2-methyl-3-(3-pyridyl)-1H-indole-1-pentanoic acid; or any otherthromboxane synthetase inhibitor which acts in a synergistic manner andis chemically compatible with the novel compounds of formula (I).

Many of the compounds of the invention also inhibit the thromboxanesynthetase enzyme in addition to their action as thromboxane receptorantagonists. Such compounds may therefore be effective in the absence ofan additional thromboxane synthetase inhibitor. The biological activityof the compounds of the invention can be demonstrated using thefollowing in vitro and in vivo assay procedures.

1. Thromboxane A₂ receptor antagonism

Spirally cut rat aortic strips, mounted for isometric tension recordingin 20 ml organ baths, are bathed in Krebs-bicarbonate solution at 37° C.Following an incubation period of 2 hours under 1 gram resting tension,the tissues are pre-treated with U-46619 (a thromboxane A2 receptoragonist) for 10 minutes, then washed and the tissues allowed toequilibriate for a further 1 hour. Cumulative doses of U-46619 over therange 1 nM-100 nM are sequentially included in the bathing fluid andincreases in the tissue tension noted.

The test compounds are incubated with the tissue for 15 minutes prior torepeating the cumulative dosing of U-46619 and the ability of thecompound to antagonize the thromboxane A₂ receptor is determined fromthe dose-response curves for U-46619 in the presence of variedconcentrations of the test compound.

2. Anaesthetised Rabbits

Thromboxane A₂ receptor antagonism is evaluated ex vivo in anaesthetisedrabbits as follows:

New Zealand White rabbits (2-2.5 kg) are anaesthetised with fentanylcitrate (0.1 89 mg) and fluanisone (6 mg) intramuscularly and midazolam(3 mg) intravenously and maintained by an intravenous infusion offentanyl citrate (0.315 mg), fluanisone (1 mg) and midazolam (1 mg) perhour. After cannulation of the trachea, a carotid artery is cannulatedfor collection of blood samples. The catheter is kept patent by thepresence within the catheter of saline containing heparin (50 μ/ml).Control carotid arterial blood samples are taken 25 and 5 minutes priorto administration of the test compound via a marginal ear vein. Twogroups of rabbits are used. The first group receives 0.01 mg/kg of thetest compound followed, at ten minute intervals, by 0.03, 0.1, 0.3, 1.0,3.0 and 10 mg/kg doses; the second group comprises the controls. Carotidarterial blood samples are taken 5 minutes after all doses. At each timepoint, a 900 μl blood sample is immediately mixed with 100 μl oftrisodium citrate (3.15%). After 90 minutes incubation at roomtemperature, this sample is mixed in equal proportions with anaggregometry buffer (J. Pharmacol. Methods, 1981, 6, 315) and brought to37° C. Electrodes for the measurement of electrical impedance are placedin the blood and U-46619 (final concentration 3 μM) is added to theblood. Antagonism of platelet thromboxane A₂ receptors by the compoundis assessed by comparing the change in electrical impedance produced byU-46619 in compound-treated rabbits with the untreated controls.

3. Conscious Dogs

Thromboxane A₂ receptor antagonism may also be evaluated ex vivo insling-restrained conscious dogs after oral (p.o.) or intravenous (i.v.)administration of a compound of the invention. The sampling and assayingprocedures employed are similar to those described for the ex vivoanaesthetised rabbit experiments.

For administration to man, in the therapy or prevention of diseases oradverse medical conditions in which TXA₂ is implicated as a causativeagent, oral dosages of the compounds would be expected to be in therange of from 20-800 mg daily for an average adult patient (70 kg). Thusfor a typical adult patient, individual tablets or capsules contain from10 to 400 mg of active compound, in a suitable pharmaceuticallyacceptable vehicle or carrier, for administration as a single dose, orin multiple doses, once or several times a day. Dosages for intravenousadministration would typically be within the range of from 5 to 400 mgper single dose required. In practice the physician will determine theactual dosage which will be most suitable for an individual patient andit will vary with the age, weight and response of the particularpatient, and with the condition being treated. The above dosages areexemplary of the average case but there can, of course, be individualinstances where higher or lower dosage ranges are merited, and such arewithin the scope of this invention.

For human use, the compounds of the formula (I) can be administeredalone, but will generally be administered in admixture with apharmaceutical carrier selected with regard to the intended route ofadministration and standard pharmaceutical practice. For example, theymay be administered orally in the form of tablets containing suchexcipients as starch or lactose, or in capsules or ovules either aloneor in admixture with excipients, or in the form of elixirs orsuspensions containing flavouring or colouring agents. They may beinjected parenterally, for example, intravenously, intramuscularly orsubcutaneously. For parenteral administration, they are best used in theform of a sterile aqueous solution which may contain other substances,for example enough salts or glucose, to make the solution isotonic withblood.

Thus the invention provides a pharmaceutical composition comprising acompound of formula (I), or a pharmaceutically acceptable salt orbiolabile ester thereof, together with a pharmaceutically acceptablediluent or carrier.

The invention also provides a compound of formula (I), or apharmaceutically acceptable salt or biolabile ester thereof, or apharmaceutical composition containing any of these entities, for use inmedicine.

The invention further includes the use of a compound of formula (I), ora pharmaceutically acceptable salt or a biolabile ester thereof, for themanufacture of a medicament for the treatment of disease conditions inwhich thromboxane A₂ is a causative agent.

In a further aspect, the invention provides a method of treating orpreventing disease conditions in which thromboxane A₂ is a causativeagent in a mammal (including a human being) which comprisesadministering to said mammal a therapeutically effective amount of acompound of formula (I), or a pharmaceutically acceptable salt, or abiolabile ester thereof.

The invention also includes any novel intermediates disclosed herein.

The synthesis of the compounds of the invention and of the intermediatesfor use in their preparation are illustrated by the following Examplesand Preparations. The purity of the compounds was routinely monitored bythin layer chromatography (TLC) using Merck Kieselgel 60 F₂₅₄ plates andthe following solvent systems (SS):

1. Dichloromethane;

2. Dichloromethane:methanol, 95:5;

3. Dichloromethane:methanol:0.880 ammonia, 90:10:1;

4. Toluene:diethylamine, 9:1;

5. Dichloromethane:methanol:0.880 ammonia, 100:20:1;

6. Dichloromethane:ethanol:ammonia, 98:2:0.2;

7. Dichloromethane:ethanol:ammonia, 90:10:1;

¹ H-Nuclear magnetic reasonance (NMR) spectra were recorded using eithera Nicolet QE-300 or a Bruker AC-300 spectrometer and were in all casesconsistent with the proposed structures. Chemical shifts are given inparts-per-million downfield from tetramethylsilane using conventionalabbreviations for designation of major peaks: s, singlet; d, doublet; t,triplet; m, multiplet and br, broad.

EXAMPLE 1

Methyl 5- 2-(4-fluorophenyl)sulphonyl!amino!ethyl!-3-(3-pyridylmethyl)-1H-indole-1-propanoate

4-Fluorobenzenesulphonyl chloride (0.346 g) was added portionwise to astirred solution of methyl5-(2-aminoethyl)-3-(3-pyridylmethyl)-1H-indole1-propanoate (0.50 g) andtriethylamine (0.33 g) in dichloromethane (5 ml) at room temperature.The mixture was stirred for 30 minutes and then washed with water anddried (MgSO₄). The solvent was evaporated and the residue waschromatographed on silica gel using dichloromethane/methanol (50:1) aseluant. The product fractions were combined and evaporated to give thetitle compound as a gum (0.59 g).

Found: C,62.89; H,5.22; N,8.15. C₂₆ H₂₆ FN₃ O₄ S requires: C,63.01;H,5.29; N,8.48%.

EXAMPLES 2 to 27

The compounds of the following formula were prepared as in Example 1using the appropriate sulphonyl chloride, sulphamoyl chloride or acylchloride and the appropriate indole compound.

    __________________________________________________________________________     ##STR21##                                                                               R.sup.3 NH                                                                    (CH.sub.2).sub.n    Solvent,                                                                            m.p.                                     Ex                                                                              R.sup.1                                                                              R.sup.2                                                                         position                                                                           R.sup.3                                                                             R.sup.7                                                                         n m x  Base  °C.                                                                       Analytical Data                       __________________________________________________________________________    2 1-imidazolyl                                                                         H 5    4-fluoro-                                                                           Me                                                                              0 2 CH.sub.2                                                                         CH.sub.2 Cl.sub.2,                                                                  Foam                                                                             Found: C, 57.93; H, 4.66;                             phenyl         Et.sub.3 N                                                                             N, 12.13;                                             sulphonyl               C.sub.22 H.sub.21 FN.sub.4                                                    O.sub.4 S requires:                                                           C, 57.88; H, 4.64;                                                            N, 12.27%.                            3 1-imidazolyl                                                                         Me                                                                              5    4-fluoro-                                                                           Me                                                                              0 2 CH.sub.2                                                                         CH.sub.2 Cl.sub.2,                                                                  Foam                                                                             Found: C, 58.45; H, 4.94;                             phenyl         Pyridine N, 11.56;                                             sulphonyl               C.sub.23 H.sub.23 FN.sub.4                                                    O.sub.4 S requires:                                                           C, 58.71; H, 4.93;                                                            N, 11.91%.                            4 4-fluorophenyl                                                                       H 5    4-fluoro-                                                                           Me                                                                              0 2 CH.sub.2                                                                         CH.sub.2 Cl.sub.2,                                                                  115-                                                                             Found: C, 61.55; H, 4.24;                             phenyl         Et.sub.3 N                                                                          118                                                                              N, 5.90.                                              sulphonyl               C.sub.29 H.sub.22 F.sub.2 N.sub.2                                             O.sub.4 S requires:                                                           C, 61.97; H, 4.58; N, 5.78%.          5 4-fluorophenyl                                                                       H 5    4-chloro-                                                                           Me                                                                              0 2 CH.sub.2                                                                         CH.sub.2 Cl.sub.2,                                                                  120-                                                                             Found: C, 60.14; H, 4.35;                             phenyl         Et.sub.3 N                                                                          123                                                                              N, 5.56;                                              sulphonyl               C.sub.25 H.sub.22 ClFN.sub.2                                                  O.sub.4 S requires:                                                           C, 59.94; H, 4.43; N, 5.59%.          6 3-pyridyl                                                                            H 5    4-chloro-                                                                           Me                                                                              0 2 direct                                                                           CH.sub.2 Cl.sub.2,                                                                  176-                                                                             Found: C, 58.96; H, 4.13;                             phenyl      link                                                                             Et.sub.3 N                                                                          178                                                                              N, 8.79;                                              sulphonyl               C.sub.23 H.sub.20 ClN.sub.2                                                   O.sub.4 S requires:                                                           C, 58.78; H, 4.29; N, 8.94%.          7 3-pyridyl                                                                            H 5    4-chloro-                                                                           Et                                                                              0 3 direct                                                                           CH.sub.2 Cl.sub.2,                                                                  209-                                                                             Found: C, 60.11; H, 4.83;                             phenyl      link                                                                             Et.sub.3 N                                                                          211                                                                              N, 8.33;                                              sulphonyl               C.sub.25 H.sub.24 ClN.sub.2                                                   O.sub.4 S requires:                                                           C, 60.29; H, 4.86; N, 8.44%.          8 3-pyridyl                                                                            H 5    4-fluoro-                                                                           Me                                                                              0 2 CH.sub.2                                                                         CH.sub.2 Cl.sub.2,                                                                  Foam                                                                             Found: C, 61.66; H, 4.63;                             phenyl         Et.sub.3 N                                                                             N, 8.95;                                              sulphonyl               C.sub.24 H.sub.22 FN.sub.2                                                    O.sub.4 S requires:                                                           C, 61.65; H, 4.74; N, 8.99%.          9 3-pyridyl                                                                            H 5    4-fluoro-                                                                           Me                                                                              0 3 CH.sub.2                                                                         CH.sub.2 Cl.sub.2,                                                                  Foam                                                                             Found: C, 63.01; H, 5.35;                             phenyl         Et.sub.3 N                                                                             N, 8.32;                                              sulphonyl               C.sub.26 H.sub.26 FN.sub.2                                                    O.sub.4 S requires:                                                           C, 63.01; H, 5.29; N, 8.48%.          10                                                                              1-imidazolyl                                                                         Me                                                                              5    4-fluoro-                                                                           Me                                                                              2 2 CH.sub.2                                                                         CH.sub.2 Cl.sub.2,                                                                  Foam                                                                             Rf. 0.55(SS3)                                         phenyl         Pyridine δ(CDCl.sub.3): 2.47(3H, s),                                             2.74-                                                 sulphonyl               2.87(4H, m), 3.24(2H, m),                                                     3.69(3H, s), 4.43(2H, t),                                                     4.62(1H, t), 5.20(2H, s),                                                     6.86(1H, s), 6.92(1H, dd),                                                    7.02(1H, s), 7.05-7.15                                                        (3H, m), 7.23(1H, d),                                                         7.49(1H, s), 7.77(2H, m).             11                                                                              1-imidazolyl                                                                         Me                                                                              4    4-fluoro-                                                                           Me                                                                              2 2 CH.sub.2                                                                         CH.sub.2 Cl.sub.2,                                                                  Foam                                                                             Found: C, 59.98; H, 5.53;                             phenyl         DMAP     N, 10.94;                                             sulphonyl               C.sub.26 H.sub.27 FN.sub.4                                                    O.sub.4 S requires:                                                           C, 60.22; H, 5.46; N, 11.24%.         12                                                                              3-pyridyl                                                                            H 5    methyl-                                                                             Me                                                                              2 2 CH.sub.2                                                                         CH.sub.2 Cl.sub.2,                                                                  Gum                                                                              Found: C, 59.37; H, 5.89;                             sulphonyl      Et.sub.3 N                                                                             N, 9.71;                                                                      C.sub.21 H.sub.25 N.sub.3 O.sub.4                                             S. O.1CH.sub.2 Cl.sub.2                                                       requires: C, 59.77; H, 5.99;                                                  N, 9.91%.                             13                                                                              3-pyridyl                                                                            H 5    dimethyl-                                                                           Me                                                                              2 2 CH.sub.2                                                                         CH.sub.2 Cl.sub.2,                                                                  Gum                                                                              Rf. 0.6(SS3)                                          amino-         DMAP/    δ(CDCl.sub.3): 2.75(6H,                                                 s),                                                   sulphonyl      Et.sub.3 N                                                                             2.82(2H, t), 2.94(2H, t),                                            (1.5:1)  3.34(2H, m), 3.67(3H, s),                                                     4.08(2H, s), 4.14(1H, t),                                                     4.42(2H, t), 6.87(1H, s),                                                     7.08(1H, d), 7.20-                                                            7.24(1H, m), 7.29-7.32                                                        (2H, m), 7.55(1H, d),                                                         8.46(1H, d), 8.60(1H, s).             14                                                                              3-pyridyl                                                                            H 5    3-methyl-                                                                           Me                                                                              2 2 CH.sub.2                                                                         CH.sub.2 Cl.sub.2,                                                                  Gum                                                                              Found: C, 68.52; H, 7.09;                             butanoyl       Et.sub.3 N                                                                             N, 9.59;                                                                      C.sub.25 H.sub.31 N.sub.3                                                     O.sub.3. 0.25CH.sub.2 Cl.sub.2                                                requires: C, 68.49; H, 7.17;                                                  N, 9.49%.                             15                                                                              3-pyridyl                                                                            H 4    4-fluoro-                                                                           Me                                                                              2 2 CH.sub.2                                                                         CH.sub.2 Cl.sub.2,                                                                  Gum                                                                              Rf. 0.6(SS3)                                          sulphonyl      Et.sub.3 N                                                                             δ(CDCl.sub.3): 2.78(2H,                                                 t),                                                                           3.00(2H, t), 3.13(2H, m),                                                     3.65(3H, s), 4.13(2H, s),                                                     4.35-4.44(3H, m), 6.72                                                        (1H, s), 6.74(1H, d), 7.07-                                                   7.24(5H, m), 7.41(1H, d),                                                     7.74(1H, m), 8.44(2H, m).             16                                                                              3-pyridyl                                                                            H 4    dimethyl-                                                                           Me                                                                              2 2 CH.sub.2                                                                         CH.sub.2 Cl.sub.2,                                                                  Gum                                                                              Rf. 0.5(SS3)                                          amino          Et.sub.3 N                                                                             δ(CDCl.sub.3): 2.70(6H,                                                 s),                                                   sulphonyl               2.79(2H, m), 3.08(2H, t),                                                     3.26(2H, m), 3.66(3H, s),                                                     4.10(1H, t), 4.23(2H, s),                                                     4.38(2H, t), 6.74(1H, s),                                                     6.88(1H, d), 7.13-7.23                                                        (3H, m), 7.46(1H, d), 8.46-                                                   8.49(2H, m).                          17                                                                              3-pyridyl                                                                            H 4    3-methyl                                                                            Me                                                                              2 2 CH.sub.2                                                                         CH.sub.2 Cl.sub.2,                                                                  113-                                                                             Found: C, 71.61; H, 7.11;                             butanoyl       Et.sub.3 N/                                                                         115                                                                              N, 9.96;                                                             DMAP(1:1)                                                                              C.sub.25 H.sub.31 N.sub.3 O.sub.3                                             requires:                                                                     C, 71.23; H, 7.41; N, 9.97%.          18                                                                              3-pyridyl                                                                            Me                                                                              5    4-fluoro-                                                                           Me                                                                              2 2 CH.sub.2                                                                         CH.sub.2 Cl.sub.2,                                                                  Gum                                                                              Rf. 0.55(SS2)                                         phenyl         Et.sub.3 N                                                                             δ(CDCl.sub.3): 2.39(3H,                                                 s),                                                   sulphonyl               2.71-2.80(4H, m), 3.17-                                                       3.24(2H, m), 3.67(3H, s),                                                     4.01(2H, s), 4.34-4.43                                                        (3H, m), 6.85(1H, d), 7.02                                                    (1H, s), 7.05-7.15(3H, m),                                                    7.20(1H, d), 7.39(1H, d),                                                     7.70-7.75(2H, m),                                                             8.40(1H, d), 8.49(1H, s).             19                                                                              3-pyridyl                                                                            Me                                                                              5    4-iodo-                                                                             Me                                                                              2 2 CH.sub.2                                                                         CH.sub.2 Cl.sub.2,                                                                  Foam                                                                             Found: C, 52.89; H, 4.55;                             phenyl-        Et.sub.3 N                                                                             N, 6.75;                                              sulphonyl               C.sub.27 H.sub.28 IN.sub.2                                                    O.sub.4 S requires:                                                           C, 52.51; H, 4.57;                                                            N, 6.81%.                             20                                                                              3-pyridyl                                                                            Me                                                                              5    4-trifluoro-                                                                        Me                                                                              2 2 CH.sub.2                                                                         CH.sub.2 Cl.sub.2,                                                                  Foam                                                                             Found: C, 59.99; H, 5.09;                             methyl         Et.sub.3 N                                                                             N, 7.34;                                              phenyl                  C.sub.28 H.sub.28 F.sub.3 N.sub.2                                             O.sub.4 S requires:                                   sulphonyl               C, 60.09; H, 5.04;                                                            N, 7.51%.                             21                                                                              3-pyridyl                                                                            Me                                                                              4    4-fluoro-                                                                           Me                                                                              2 2 CH.sub.2                                                                         CH.sub.2 Cl.sub.2,                                                                  Gum                                                                              Rf. 0.7(SS3)                                          phenyl         Et.sub.3 N                                                                             δ(CDCl.sub.3): 2.35(3H,                                                 s),                                                   sulphonyl               2.76(2H, t), 2.89(2H, t),                                                     3.05(2H, m), 3.68(3H, s),                                                     4.14(2H, s), 4.39-4.48                                                        (3H, m), 6.70(1H, d), 7.05-                                                   7.12(4H, m), 7.20-                                                            7.26(2H, m), 7.68-                                                            7.72(2H, m), 8.33-8.38                                                        (2H, m).                              22                                                                              H      H 5    4-chloro-                                                                           Me                                                                              O 2 direct                                                                           CH.sub.2 Cl.sub.2,                                                                  Gum                                                                              Found: C, 55.21; H, 4.36;                             phenyl      link                                                                             Et.sub.3 N                                                                             N, 6.74;                                              sulphonyl               C.sub.18 H.sub.17 ClN.sub.2                                                   O.sub.4 S requires:                                                           C, 55.04; H, 4.36; N, 7.13%.          23                                                                              H      H 5    4-fluoro-                                                                           Me                                                                              O 2 direct                                                                           CH.sub.2 Cl.sub.2,                                                                  Gum                                                                              Found: C, 57.41; H, 4.61;                             phenyl      link                                                                             Et.sub.3 N                                                                             N, 7.32;                                              sulphonyl               C.sub.18 H.sub.17 FN.sub.2                                                    O.sub.4 S requires:                                                           C, 57.44; H, 4.55; N, 7.44%.          24                                                                              4-fluoro-                                                                            H 5    Phenyl-                                                                             Me                                                                              O 2 CH.sub.2                                                                         CH.sub.2 Cl.sub.2,                                                                  109-                                                                             Found: C, 64.65; H, 5.05;               phenyl        sulphonyl      Et.sub.3 N                                                                          112                                                                              N, 5.91;                                                                      C.sub.25 H.sub.23 FN.sub.2                                                    O.sub.4 S requires:                                                           C, 64.36; H, 4.97; N, 6.00%.          25                                                                              4-fluoro-                                                                            H 5    4-trifluoro-                                                                        Me                                                                              O 2 CH.sub.2                                                                         CH.sub.2 Cl.sub.2,                                                                  100-                                                                             Found: C, 58.30; H, 4.09;               phenyl        methyl-        Et.sub.3 N                                                                          103                                                                              N, 5.38;                                              phenyl-                 C.sub.26 H.sub.22 F.sub.4 N.sub.2                                             O.sub.4 S requires:                                   sulphonyl               C, 58.42; H, 4.15; N, 5.24%.          26                                                                              4-fluoro-                                                                            H 5    4-methoxy-                                                                          Me                                                                              O 2 CH.sub.2                                                                         CH.sub.2 Cl.sub.2,                                                                  161-                                                                             Found: C, 62.91; H, 5.00;               phenyl        phenyl-        Et.sub.3 N                                                                          162                                                                              N, 5.43;                                              sulphonyl               C.sub.26 H.sub.25 FN.sub.2                                                    O.sub.5 S requires:                                                           C, 62.89; H, 5.07; N, 5.64%.          27                                                                              4-fluoro-                                                                            H 5    4-methyl-                                                                           Me                                                                              O 2 CH.sub.2                                                                         CH.sub.2 Cl.sub.2,                                                                  145-                                                                             Found: C, 65.06; H, 5.32;               phenyl        phenyl-        Et.sub.3 N                                                                          148                                                                              N, 5.85;                                              sulphonyl               C.sub.26 H.sub.25 FN.sub.2                                                    O.sub.4 S requires:                                                           C, 64.98; H, 5.24; N,                 __________________________________________________________________________                                            5.83%.                            

EXAMPLE 28

Methyl 5-(2-cyclopropyl)acetyl!amino!ethyl-3-(3-pyridylmethyl))-1H-indole-1-propanoate

A mixture of cyclopropylacetic acid (0.25 g) and carbonyldiimidazole(0.288g) in dry tetrahydrofuran (9 ml) was heated under reflux untilevolution ofCO₂ ceased. A solution of methyl5-(2-aminoethyl)-3-(3-pyridylmethyl)-1H-indole-1-propanoate (0.50 g) indry dichloromethane (5 ml) was added and the solution was stirred atroom temperature for 56 hours and then evaporated. The residue waspartitioned between ethyl acetate and water. The organic layer waswashed twice with water, dried (MgSO₄) and evaporated. The residue waschromatographed on silica gel. Elution with dichloromethane gavestarting material, and then further elution withdichloromethane/methanol (19:1) gave pure product. The product fractionswere evaporated to give the title compound as a gum (0.497 g). Rf. 0.7(SS3).

δ(CDCl₃): 0.10(2H,m), 0.48(2H,m), 0.85(1H,m), 2.10(2H,d), 2.82(2H,t)2.91(2H,t), 3.57(2H,m), 3.67(3H,s), 4.07(2H,s), 4.42(2H,t), 5.90(1H,br),6.85(1H,s), 7.08(1H,d), 7.22(1H,m), 7.29-7.32(2H,m), 7.57(1H,d),8.48(1H,d), 8.57(1H,s).

EXAMPLE 29 5-(4-Fluorophenyl)sulphonyl!amino-3-(3-pyridylmethyl)-1H-indole-1-propanoicacid

A mixture of methyl 5-(4-fluorophenyl)sulphonyl!-amino-3-(3-pyridylmethyl)-1H-indole-1-propanoate(the product of Example 8) ((1.10 g), sodium hydroxide (0.47 g),methanol (2 ml) and water (10 ml) was heated under reflux for 75 minutesand then evaporated to a small volume. The solution was acidified withacetic acid to give a gum which solidified on scratching. The solid wasfiltered off, washed with water and dried. Crystallisation from ethylacetate/methanol gave the title compound (0.64 g), m.p. 214°-215° C.Found: C,61.18; H,4.23; N,9.28. C₂₃ H₂₀ FN₃ O₄ S requires: C,60.91;H,4.44; N,9.26%.

EXAMPLES 30-56

The procedure of Example 29 was repeated but using the appropriatestartingmaterial to produce compounds of the following formula given inthe following Table:

    __________________________________________________________________________     ##STR22##                                                                               R.sup.3 NH(CH.sub.2).sub.n                                                                         m.p.                                          Ex                                                                              R.sup.1                                                                              R.sup.2                                                                         position                                                                            R.sup.3 n m x  °C.                                                                         Analytical Data                          __________________________________________________________________________    30                                                                              1-imidazolyl                                                                         H 5     4-fluorophenyl                                                                        0 2 CH.sub.2                                                                         208- Found: C, 57.47; H, 4.15; N, 12.60;                       sulphonyl      210  C.sub.21 H.sub.19 FN.sub.4 O.sub.4 S                                          requires: C, 57.00;                                                           H, 4.33; N, 12.66%.                      31                                                                              1-imidazolyl                                                                         Me                                                                              5     4-fluorophenyl                                                                        0 2 CH.sub.2                                                                         Foam Rf. 0.1(SS3)                                              sulphonyl           δ(CDCl.sub.3): 2.44(3H, s),                                             2.60(2H, t),                                                                  4.27(2H, t), 5.19(2H, s), 6.77(1H,                                            d),                                                                           6.82(1H, s), 6.89(1H, s), 7.18(1H,                                            s),                                                                           7.29-7.33(3H, m), 7.58(1H, s),                                                7.66-                                                                         7.70(2H, m), 9.97(1H, s).                32                                                                              4-fluorophenyl                                                                       H 5     4-fluorophenyl                                                                        0 2 CH.sub.2                                                                         185- Found: C, 60.78; H, 4.19; N, 5.74;                        sulphonyl      188  C.sub.24 H.sub.20 F.sub.2 N.sub.2                                             O.sub.4 S requires: C, 61.27;                                                 H, 4.28; N, 5.75%.                       33                                                                              4-fluorophenyl                                                                       H 5     4-chlorophenyl                                                                        0 2 CH.sub.2                                                                         144- Found: C, 59.33; H, 3.93; N, 5.55;                        sulphonyl      147  C.sub.24 H.sub.20 ClFN.sub.2 O.sub.4                                          S requires: C, 59.20;                                                         H, 4.14; N, 5.75%.                       34                                                                              3-pyridyl                                                                            H 5     4-chlorophenyl                                                                        0 2 direct                                                                           235- Found: C, 58.28; H, 3.71; N, 9.04;                        sulphonyl   link                                                                             237  C.sub.22 H.sub.18 ClN.sub.3 O.sub.4                                           S requires: C, 57.95;                                                         H, 3.98; N, 9.22%.                       35                                                                              3-pyridyl                                                                            H 5     4-chlorophenyl                                                                        0 3 direct                                                                           199- Found: C, 58.63; H, 4.16; N, 8.81;                        sulphonyl   link                                                                             201  C.sub.23 H.sub.20 ClN.sub.3 O.sub.4                                           S requires: C, 58.78;                                                         H, 4.29; N, 8.94%.                       36                                                                              3-pyridyl                                                                            H 5     4-fluorophenyl                                                                        0 3 CH.sub.2                                                                         154- Found: C, 61.80; H, 4.68; N, 8.91;                        sulphonyl      156  C.sub.24 H.sub.22 FN.sub.3 O.sub.4 S                                          requires: C, 61.65;                                                           H, 4.74; N, 8.99%.                       37                                                                              1-imidazolyl                                                                         Me                                                                              5     4-fluorophenyl                                                                        2 2 CH.sub.2                                                                         165- Found: C, 58.99; H, 5.40; N, 10.96;                       sulphonyl      167  C.sub.24 H.sub.25 FN.sub.4 O.sub.4 S                                          requires: C, 59.49;                                                           H, 5.70; N, 11.57%.                      38                                                                              1-imidazolyl                                                                         Me                                                                              4     4-fluorophenyl-                                                                       2 2 CH.sub.2                                                                         Foam Rf. 0.15(SS3).                                            sulphonyl           δ(DMSOd.sub.6): 2.45(3H, s),                                            2.63(2H, t),                                                                  2.79(2H, t), 2.85(2H, m), 4.37(2H,                                            t),                                                                           5.24(2H, s), 6.72(1H, d), 6.82(1H,                                            s),                                                                           6.88(1H, s), 6.98(1H, dd),                                                    7.30-7.40                                                                     (3H, m), 7.45(1H, s), 7.79(2H, m),                                            8.91                                                                          (1H, t).                                 39                                                                              3-pyridyl                                                                            H 5     4-fluorophenyl-                                                                       2 2 CH.sub.2                                                                         158-160                                                                            Found: C, 61.98; H, 5.26; N, 8.52;                        sulphonyl           C.sub.25 H.sub.24 FN.sub.3 O.sub.4 S                                          requires: C, 62.35;                                                           H, 5.02; N, 8.73%.                       40                                                                              3-pyridyl                                                                            H 5     methylsulphonyl                                                                       2 2 CH.sub.2                                                                         180- Found: C, 60.07; H, 5.78; N, 10.25;                                      182.5                                                                              C.sub.20 H.sub.23 N.sub.3 O.sub.4 S                                           requires: C, 59.83;                                                           H, 5.77; N, 10.47%.                      41                                                                              3-pyridyl                                                                            H 5     dimethylamino-                                                                        2 2 CH.sub.2                                                                         160-161                                                                            Found: C, 58.88; H, 5.81; N, 12.93;                       sulphonyl           C.sub.21 H.sub.25 N.sub.4 O.sub.4 S                                           requires: C, 58.58;                                                           H, 6.09; N, 13.02%.                      42                                                                              3-pyridyl                                                                            H 5     3-methyl-                                                                             2 2 CH.sub.2                                                                         171- Found: C, 71.03; H, 6.79; N, 10.27;                       butanoyl       172.5                                                                              C.sub.24 H.sub.20 N.sub.3 O.sub.3                                             requires: C, 70.73; H, 7.17;                                                  N, 10.31%.                               43                                                                              3-pyridyl                                                                            H 5     cyclopropyl-                                                                          2 2 CH.sub.2                                                                         159- Found: C, 71.17; H, 6.72; N, 9.89;                        acetyl         161  C.sub.24 H.sub.27 N.sub.3 O.sub.3                                             requires: C, 71.08; H, 6.71;                                                  N, 10.36%.                               44                                                                              3-pyridyl                                                                            H 4     4-fluorophenyl                                                                        2 2 CH.sub.2                                                                          93-95                                                                             Found: C, 62.20; H, 5.00; N, 8.76;                        sulphonyl           C.sub.25 H.sub.24 FN.sub.3 O.sub.4 S                                          requires: C, 62.35;                                                           H, 5.02; N, 8.73%.                       45                                                                              3-pyridyl                                                                            H 4     dimethylamino                                                                         2 2 CH.sub.2                                                                         179- Found: C, 58.96; H, 6.00; N, 12.56;                       sulphonyl      181  C.sub.21 H.sub.26 N.sub.4 O.sub.4 S                                           requires: C, 58.58; H, 6.09;                                                  N, 13.02%.                               46                                                                              3-pyridyl                                                                            H 4     3-methyl-                                                                             2 2 CH.sub.2                                                                         195- Found: C, 70.97; H, 7.11; N, 10.26;                       butanoyl       196  C.sub.24 H.sub.29 N.sub.3 O.sub.3                                             requires: C, 70.73; H, 7.17;                                                  N, 10.31%.                               47                                                                              3-pyridyl                                                                            Me                                                                              5     4-fluorophenyl                                                                        2 2 CH.sub.2                                                                         197- Found: C, 62.49; H, 5.07; N, 8.15;                        sulphonyl      199  C.sub.26 H.sub.26 FN.sub.3 O.sub.4 S                                          requires: C, 63.01;                                                           H, 5.29; N, 8.48%.                       48                                                                              3-pyridyl                                                                            Me                                                                              5     4-iodophenyl                                                                          2 2 CH.sub.2                                                                         173- Found: C, 52.02; H, 4.27; N, 6.81;                        sulphonyl      176  C.sub.26 H.sub.26 IN.sub.3 O.sub.4 S                                          requires: C, 51.74; H, 4.34;                                                  N, 6.96%.                                49                                                                              3-pyridyl                                                                            Me                                                                              5     4-trifluoro-                                                                          2 2 CH.sub.2                                                                         185- Found: C, 59.51; H, 4.84; N, 7.53;                        methylphenyl-  187  C.sub.27 H.sub.26 F.sub.3 NO.sub.4 S                                          requires: C, 59.44;                                       sulphonyl           H, 4.80; N, 7.70%.                       50                                                                              3-pyridyl                                                                            Me                                                                              4     4-fluorophenyl                                                                        2 2 CH.sub.2                                                                         218- Found: C, 63.07; H, 5.19; N, 8.38;                        sulphonyl      220  C.sub.26 H.sub.26 FN.sub.3 O.sub.4 S                                          requires: C, 63.01;                                                           H, 5.29; N, 8.38%.                       51                                                                              H      H 5     4-chlorophenyl                                                                        0 2 direct                                                                           174- Found: C, 54.29; H, 4.12; N, 7.16;                        sulphonyl   link                                                                             176  C.sub.17 H.sub.15 ClN.sub.2 O.sub.4                                           S requires: C, 53.90;                                                         H, 3.99; N, 7.39%.                       52                                                                              H      H 5     4-fluorophenyl                                                                        0 2 direct                                                                           140- Found: C, 55.91; H, 4.08; N, 7.30;                        sulphonyl   link                                                                             141  C.sub.17 H.sub.15 FN.sub.2 O.sub.4 S                                          requires: C, 56.33;                                                           H, 4.17; N, 7.73%.                       53                                                                              4-fluoro-                                                                            H 5     phenyl- O 2 CH.sub.2                                                                         178- Found: C, 63.37; H, 4.59; N, 5.90;         phenyl         sulphonyl      181  C.sub.24 H.sub.21 FN.sub.2 O.sub.4 S                                          requires: C, 63.70;                                                           H, 4.68; N, 6.19%.                       54                                                                              4-fluoro-                                                                            H 5     4-trifluoro-                                                                          O 2 CH.sub.2                                                                         171- Found: C, 58.14; H, 3.61; N, 5.01;         phenyl         methylphenyl-  175  C.sub.25 H.sub.20 F.sub.4 N.sub.2                                             O.sub.4 S requires: C, 57.69;                             sulphonyl           H, 3.87; N, 5.38%.                       55                                                                              4-fluoro-                                                                            H 5     4-methoxy-                                                                            O 2 CH.sub.2                                                                         166- Found: C, 62.14; H, 4.73; N, 5.93;         phenyl         phenyl-        168  C.sub.25 H.sub.23 FN.sub.2 O.sub.5 S                                          requires: C, 62.23;                                       sulphonyl           H, 4.80; N, 5.81%.                       56                                                                              4-fluoro-                                                                            H 5     4-methyl-                                                                             O 2 CH.sub.2                                                                         203- Found: C, 64.12; H, 4.79; N, 5.95;         phenyl         phenyl-        206  C.sub.25 H.sub.23 FN.sub.2 O.sub.4 S                                          requires: C, 64.36;                                       sulphonyl           H, 4.97; N, 6.00%.                       __________________________________________________________________________

EXAMPLE 57 1,2-Dimethyl-5-(4-fluorophenyl)sulphonyl!amino-1H-indole-1-propanoic acid

A solution of 5-(4-fluorophenyl)sulphonyl!amino-3-(1H-imidazol-1-ylmethyl)-2-methyl-1H-indole-1-propanoicacid (0.30 g) in ethanol (5 ml) and acetic acid (5 ml) was hydrogenatedfor 24 hours at 50° C. and 4.5 atm. in the presence of 10% palladium oncarbon (30 mg). The mixture was filtered and the residue was washed withethanol. The filtrate and washings were combined and evaporated, and theresidue was partitioned between ethyl acetate and water. The organiclayer was washed twice with water and dried(MgSO₄). The solvent wasevaporated and the residue was chromatographed on silica gel, usingdichloromethane/methanol (19:1) as eluant. The product fractions werecombined and evaporated to give the title compound as a gum (0.035 g),Rf. 0.75(SS7). δ(DMSOd₆): 1.96(3H,s), 2.25(3H,s), ca 2.48(2H,t),4.20(2H,t), 6.70(1H,d), 6.98(1H,s),7.15(1H,d), 7.26(2H,m), 7.66(2H,m),9.71 (1H,s).

EXAMPLE 58

    ______________________________________                                        Pharmaceutical Capsules mg/capsule                                            ______________________________________                                        Thromboxane A.sub.2  Antagonist                                                                       50.0                                                  Thromboxane Synthetase Inhibitor                                                                      150.0                                                 Starch                  49.0                                                  Magnesium stereate BP   1.0                                                                           250    mg                                             ______________________________________                                    

The thromboxane A₂ antagonist and the thromboxane synethase inhibitorare sieved and blended with the starch and the excipients. The mix isfilled into size No. 2 hard gelatin capsules, using suitable machinery.Capsules of other strengths or with different ratios of activeingredientsmay be prepared in a similar manner.

Regarding toxicity, the compounds of Examples 33,41,42,46 and 49 haveeach been administered acutely to dogs at doses up to 10 mg/kg orally.No signsof toxicity were observed.

PREPARATION 1 3-(1H-Imidazol-1-ylmethyl)-5-nitro-1H-indole

A mixture of N,N-dimethyl-5-nitro-1H-indole-3-methanamine (J.Med, Chem,9, 140,(1966)) (9.10 g) and imidazole (2.96 g) in xylene (120 ml) washeated under reflux for 2.5 hours and then cooled. The solid wasfiltered off, washed with ether and dried to give the title compound(9.40 g), m.p. 230°-232° C. (from ethyl acetate/methanol). Found:C,59.85; H,4.39; N,22.80. C₁₂ H₁₀ N₄ O₂ requires: C,59.50; H,4.16;N,23.13%.

PREPARATION 2 3-(1H-Imidazol-1-ylmethyl)-2-methyl-5-nitro-1H-indole

Treatment of 2, N,N-trimethyl-5-nitro-1H-indole-3-methanamine(J.Org.Chem.,28,2921(1963)) (5.60 g) with imidazole (1.90 g) in xylene(100 ml) according to the method of Preparation 1 gave the titlecompound (5.50 g),m.p. 240°-242° C. Found: C,61.02; H,4.41; N,21.68. C₁₃H₁₂ N₄ O₂ requires: C,60.92; H,4.72; N,21.87%.

PREPARATION 3 5-Nitro-3-(3-pyridylmethyl)-1H-indole

a) 3-(3-Pyridyl)propanal

Dimethylsulphoxide (18.9 ml) in dry dichloromethane (120 ml) was addedover20 minutes to a stirred solution of oxalyl chloride (11.55 ml) indry dichloromethane (225 ml) at -70° C. The mixture was stirred at -70°C. for 10 minutes and then a solution of 3-(3-pyridyl)propanol(16.56 g)in dry dichloromethane (120 ml) was added with stirring over 20 minutes.Stirring was continued at -70° C. for a further 20 minutesand thentriethylamine (50.55 ml) was added dropwise and the temperature wasallowed to rise to room temperature. Water (200 ml) was added and thelayers were separated. The organic layer was washed twice with water,dried (MgSO₄) and evaporated. The residue was distilled to give thetitle compound as an oil (8.80 g), b.p. 88°-92° C. @ 0.3 mm., Rf. 0.15(SS2). δ(CDCl₃): 2.80(3H,t), 2.93(3H,t), 7.18-7.21 (1H,m), 7.50(1H,d),8.40-8.45(2H,m), 9.80(1H,s).

b) 3-(3-Pyridyl)propanal-4-nitrophenylhydrazone

3-(3-Pyridyl)propanal (8.50 g) was added to a stirred suspension of4-nitrophenylhydrazine (9.62 g) in ether 150 ml. After a minute anorange-brown oil formed which solidified on further stirring. The solidwas filtered off to give the title compound pure enough for furtherreaction (14.05 g), m.p. 146°-147° C. (from ethyl acetate/methanol).Found: C,62.12; H,5.02; N,20.36. C₁₄ H₁₄ N₄ O₂ requires: C,62.21;H,5.22; N,20.73%.

c) 5-Nitro-3-(3-pyridylmethyl)-1H-indole

The above hydrazone (15 g) was added portionwise to a stirred mixture ofpolyphosphoric acid (60 g) and toluene (180 ml). The mixture was thenheated at 110° C. with stirring for 1 hour and then cooled, poured intowater and basified with concentrated aqueous ammonia solution. Theaqueous layer was separated and extracted three times with ethylacetate. The organic layers were combined, washed with water and dried(MgSO₄). The solvent was evaporated and the residue was chromatographedon silica gel. Elution with dichloromethane/methanol (40:1), graduallyincreasing the polarity to 25:1, gave the title compound(9.4 g), m.p.154°-156° C. (from ethyl acetate). Found: C,66.68; H,4.19; N,16.61. C₁₄H₁₁ N₃ O₂ requires: C,66.39; H,4.38; N,16.59%.

PREPARATION 4 5-Nitro-3-(3-pyridyl)-1H-indole

a) 3-(2-EZ-methoxyethenyl)pyridine

Phenyllithium (111 ml of 1.8M solution in ether) was added dropwise to astirred suspension of (methoxymethyl) triphenylphosphonium chloride(68.6 g) in dry ether (600 ml) at -50° C. The mixture was stirred at-50° C. for 2 hours and then allowed to reach 0° C. over 30 minutes.3-Pyridinecarboxaldehyde (10.70 g) was added dropwise with stirring, andthe mixture was stirred at room temperature for 18 hours. Anexcess ofammonium chloride solution was then added and the layers were separated.The aqueous layer was separated and washed with ether, and the organiclayers were combined and dried (MgSO₄). The solvent was evaporated andthe residue was chromatographed on silica gel initially using ethylacetate/hexane (1:4) as eluant. The polarity was gradually increased toethyl acetate/hexane (1:1) to give the pure product as an oil(8.82 g)which was used directly in the next stage.

b) 3-Pyridineacetaldehyde-4-nitrophenylhydrazone

A solution of 3-(2-EZ-methoxyethenyl)pyridine (3.43 g) in ethanol (15ml) and 2N hydrochloric acid (25 ml) was heated under reflux for 1 hourand then cooled. 4-nitrophenylhydrazine (3.89 g) was added portionwisewith stirring to give a solution which deposited a yellow solid. Themixture was cooled in ice and the solid was filtered off, washed withisopropanol,ether and then dried to give the title compound (5.32 g),m.p. 212°-214° C. Found: C,53.54; H,4.51; N,19.00. C₁₃ H₁₂ N₄ O₂requires: C,53.34; H,4.48; N,19.14%.

5-Nitro-3-pyridyl-1H-indole

The above hydrazone (4.30 g) was added to ice-cooled concentratedsulphuricacid (43 ml) at such a rate that the temperature did not riseabove 20° C. The mixture was stirred at room temperature for 1 hour andwas then stirred at 30° C. for a further 1 hour. It was carefully pouredinto 500 ml of ice water and the solution was basified with concentratedaqueous ammonia solution with cooling. The mixture was extracted twicewith ethyl acetate and the combined extracts were washed with water anddried (MgSO₄). The solvent was evaporated and the residue waschromatographed on silica gel. Elution with ethyl acetate followed byethyl acetate/methanol (19:1) gave the title compound (1.25 g),m.p. >265° C. Found: C,65.34; H,3.41; N,17.69. C₁₃ H₁₉ N₃ O₂ requires:C,65.26; H,3.79; N,17.57%.

PREPARATION 5 3-(4-Fluorophenylmethyl)-5-nitro-1H-indole

a) 3-(4-Fluorophenyl)propanal

Di-isobutylaluminium hydride (75 ml of 1.0M solution in toluene) wasadded dropwise to a stirred solution of ethyl(4-fluorophenyl)-propanoate (J.Org.Chem.,31, 1524 (1966)) (11.84 g) intoluene (130 ml) at -70°C. The solution was stirred at -70° C. for 90minutes, then ca 100 ml of 15% ammonium chloride solution was addeddropwise and the temperature was allowed to reach room temperature. Theorganic layer was separated, dried (Na₂ SO₄) and evaporated to give anoil which was chromatographed on silica gel. Elution withdichloromethane/hexane (3:1) gave the title compound as an oil (7.05 g),Rf. 0.7(SS1).

δ(CDCl₃): 2.77(2H,t), 2.93(2H,t), 6.94-7.00(2H,m), 7.13-7.17(2H,m)9.81(1H,s).

b) 3-(4-Fluorophenyl)propanal-4-nitrophenylhydrazone

A solution of 3-(4-fluorophenyl)propanal (7.0 g) in ether (50 ml) wasaddedto a stirred suspension of 4-nitrophenylhydrazine (7.0 g) in ether(1 50 ml), followed by sufficient ethyl acetate to achieve a clearsolution. Thesolution was filtered and evaporated and the residue wascrystallised from ethyl acetate/hexane to give the title compound (5.48g), m.p. 125°-127° C. Found: C,62.81; H,4.87; N,14.44. C₁₅ H₁₄ FN₃ O₂requires: C,62.71; H,4.91; N,14.63%.

Evaporation of the filtrate and trituration of the residue with hexanegavea further 5.39 g of title compound pure enough for further reaction.

c) 3-(4-Fluorophenylmethyl)-5-nitro-1H-indole

The above hydrazone (1 0.5 g) was added portionwise to a stirred mixtureofpolyphosphoric acid (45 g) and toluene (120 ml) at 40° C. Theresulting mixture was stirred at 105°-110° C. for 75 minutesand thencooled. The toluene layer was decanted off and the residue was pouredinto water. The mixture was extracted twice with toluene and all theorganic layers were combined, washed with water and dried (Na₂ SO₄).Evaporation of the solvent gave a solid which was crystallised fromethyl acetate to give the title compound (2.20 g), m.p. 142°-144° C.Found: C,66.44; H,3.68; N,10.00. C₁₅ H₁₁ FN₂ O₂ requires: C,66.66;H,4.10; N,10.37%.

PREPARATION 6 5-Bromo-3-(3-pyridylmethyl)-1H-indole

Methyl magnesium iodide (4.0 ml of 3M solution in ether) was added over5 minutes to a stirred solution of 5-bromo-1H-in dole (1.96 g) in drytetrahydrofuran (25 ml) at 2° C., the resulting suspension was stirredat room temperature for 45 minutes. Separately, a solution of3-(chloromethyl)pyridine was prepared by partitioning3-(chloromethyl)pyridine hydrochloride (1.97 g) between water anddichloromethane followed by dropwise addition of triethylamine withshaking until the pH of the aqueous layer was >7. The layers wereseparated and the aqueous layer was extracted with dichloromethane. Theorganic layers were combined, dried (MgSO₄) and evaporated to ca 25 ml.The solution was dried for a further 20 minutes by the addition of 3Amolecular sieves. It was then added dropwise with stirring to thesuspension of the indole Grignard reagent. The mixture was heated at 75°C. for 2 hours with stirring and then allowed to cool to roomtemperature. A solution of ammonium chloride (1.0 g) in water (30 ml)was added with stirring and the resulting mixture was extracted severaltimes with ethyl acetate. The combined organic layers were washed withwater, dried (MgSO₄) and evaporated. The residue was chromatographed onsilica gel using dichloromethane/methanol (50:1) as eluent. Impurity waseluted first followed by pure product. The product fractions werecombinedand evaporated and the residue was crystallised from ether togive the title compound (0.798 g), m.p. 126°-128° C. Found: C,58.76;H,3.92; N,9.67. C₁₄ H₁₁ BrN₂ requires: C,58.55; H,3.86; N,9.76%.

PREPARATION 7 4-Bromo-3-(3-pyridylmethyl)-1H-indole

Treatment of 4-bromo-1H-indole (J.Org.Chem., 48 2066(1983)) (16.95 g)with methyl magnesium bromide (34.6 ml of 3M solution in ether) followedby a dichloromethane solution of 3-(chloromethyl)pyridine (prepared from17.02 g of 3-(chloromethyl)pyridine hydrochloride) according to themethod of Preparation 6 gave the title compound (7.80 g), m.p. 173°-174°C. Found: C,58.90; H,3.88; N,9.80. C,₁₄ H₁₁ BrN₂ requires: C,58.55;H,3.86; N,9.76%.

PREPARATION 8 5-Bromo-2-methyl-3-(3-pyridylmethyl)-1H-indole

A solution of 5-bromo-2-methyl-1H-indole (J. Chem. Soc., 1428 (1965))(2.0 g) and 3-pyridinecarboxaldehyde (1.02 g) in dry dichloromethane (20ml) was added dropwise over 10 minutes to a stirred solution oftriethylsilane(3.30 g) in trifluoroacetic acid (20 ml) at 0° C. Thesolution was stirred at 0° C. for 30 minutes and then evaporated undervacuum, keeping the temperature below 35° C. The residue was dissolvedin dichloromethane, and the solution was washed with 2N sodiumhydroxide, water and dried (MgSO₄). The solution was evaporated and theresidue was chromatographed on silica gel, usingdichloromethane/methanol (50:1) as eluent. The product fractions werecombined and evaporated, and the residue was crystallised from ether togive the title compound (2.15 g), m.p. 188°-190° C. Found: C,59.62;H,4.43; N,9.26. C₁₅ H₁₃ BrN₂ requires: C,59.82; H,4.35; N,9.30%.

PREPARATION 9 4-Bromo-2-methyl-1H-indole and 6-bromo-2-methyl-1H-indole

3-Bromophenylhydrazine hydrochloride (26.5 g) was partitioned betweenetherand excess 2N sodium hydroxide solution. The ether layer wasseparated, washed with brine, dried (MgSO₄) and evaporated. The residuewas redissolved in ether (25 ml) and the solution was cooled in ice.Acetone (25 ml) was added and the mixture was allowed to stand for 20minutes and then evaporated. The residue was dissolved in acetone (25ml), the solution was evaporated and the residue azeotroped with xylene.The residue was dissolved in xylene (30 ml) and the solution was addeddropwise to stirred polyphosphoric acid (200 g) at 90° C. The mixturewas stirred at 100° C. for 4 hours and then cooled and poured into icewater with stirring. The mixture was extracted twice with ether, and thecombined extracts were washed with brine and dried (MgSO₄). The solventwas evaporated and the residue was chromatographed on silica gel usingdichloromethane/hexane (1:4) as eluent. The product fractions werecombined and evaporated, and the residue was crystallised twice fromhexane to give 6-bromo-2-methyl-1H-indole (8.70 g), m.p. 132°-134° C.δ(CDCl₃): 2.38(3H,s), 6.15(1H,s), 7.12(1H,dd), 7.32(1H,d), 7.36(1H,d),7.77(1H,br).

The hexane filtrates were combined and evaporated, and the residue waschromatographed as before to give an oil (8.35 g) shown by nmr toconsist of a mixture of 4-bromo-2-methyl-1H-indole and6-bromo-2-methyl-1H-indole in the ratio 3:1.

δ(CDCl₃) for the 4-bromo isomer: 2.45(3H,s), 6.29(1H,s), 6.95(1H,dd),7.21-7.27(2H,m), 7.96(1H,br).

PREPARATION 10 Benzyl (E)-3-(2-methyl-1H-indol-4-yl)-2-propenoate

A mixture of 4-bromo-2-methyl-1H-indole (containing 25% of the 6-bromoisomer) (8.30 g), palladium (II) acetate (0.45 g), tri-o-tolylphosphine(1.22 g), benzyl acrylate (9.76 g) and triethylamine (8.36 ml) inacetonitrile (8 ml) was heated in an oil bath at 140° C. under anatmosphere of nitrogen for 2 hours. The mixture was cooled andpartitionedbetween dichloromethane and water. The organic layer wasseparated, washed three times with water and dried (MgSO₄). Evaporationof the solvent gave an oil which was chromatographed on silica gel.Elution with dichloromethane/hexane (1:1) first gave impurity followedby pure product.The product fractions were evaporated and the residuewas triturated with ether to give the title compound (6.60 g), m.p.135°-136° C.Found: C,77.98; H,6.10; N,4.71. C₁₉ H₁₇ NO₂ requires:C,78.33; H,5.88; N,4.81%. Further elution with dichloromethane/hexane(4:1) gave benzyl (E)-3-(2-methyl-1H-indol-6-yl)-2-propenoate (2.0 g),m.p. 164°-165° C. Found: C,78.53; H,6.06; N,4.74. C₁₉ H₁₇ NO₂ requires:C,78.33; H,5.88; N,4.81%.

The following compounds were prepared similarly.

    __________________________________________________________________________    Structure                        m.p. °C.                                                                    Analytical Data                         __________________________________________________________________________     ##STR23##                       139-141                                                                            Found: C, 77.74; H, 5.92; N, 4.52;                                            C.sub.19 H.sub.17 NO.sub.2                                                    requires: C, 78.33; H, 5.88; N,                                               4.81%.                                   ##STR24##                       160-161                                                                            Found: C, 75.47; H, 6.46; N, 8.33;                                            C.sub.21 H.sub.22 N.sub.2 O.sub.2                                             requires: C, 75.42; H, 6.63; N,                                               8.38%.                                   ##STR25##                       121-124                                                                            Found: C, 75.53; H, 6.87; N, 8.12;                                            C.sub.22 H.sub.24 N.sub.2 O.sub.2                                             requires C, 75.83; H, 6.94; N,                                                8.04%.                                   ##STR26##                       146-148                                                                            Found: C, 75.12; H, 6.40; N, 8.29;                                            C.sub.21 H.sub.22 N.sub.2 O.sub.2                                             requires: C, 75.42; H, 6.63; N,                                               8.38%.                                  __________________________________________________________________________

PREPARATION 11 Benzyl (E)-3-2-methyl-3-(3-pyridylmethyl)-1H-indol-4-yl!-2-propenoate

A solution of benzyl (E)-3- 2-methyl-1H-indol-4-yl!-2-propenoate (4.75g) and pyridine-3-carboxaldehyde (2.10 g) in dry dichloromethane (45 ml)was added dropwise to a stirred solution of triethylsilane (7.82 ml) intrifluoroacetic acid (40 ml) at 0° C. The solution was stirred, allowingthe temperature to rise to room temperature, for 45 minutes and thenevaporated. The residue was partitioned between dichloromethane anddilute aqueous ammonia solution. The aqueous layer was extracted withdichloromethane, and the combined organic layers were washed with waterand dried (MgSO₄). The solvent was evaporated and the residue waschromatographed on silica gel. Elution with dichloromethane gaveimpurity,and further elution with dichloromethane/methanol (19:1) gavepure product.The product fractions were evaporated and the residue wastriturated with ether to give the title compound (2.19 g), m.p.180°-182° C., Rf. 0.35(SS1).

δ(CDCl₃): 2.43(3H,s), 4.21(2H,s), 5.21(2H,s), 6.30(1H,d),7.01-7.11(2H,m), 7.28-7.42(8H,m), 8.19(1H,d), 8.22(1H,s), 8.38(2H,s).

PREPARATION 12 Benzyl (E)-3-3-(dimethylaminomethyl)-2-methyl-1H-indol-5-yl!-2-propenoate

Dimethylamine (3.35 ml of 33% solution in methylated spirit) was addedto astirred mixture of benzyl(E)-3-(2-methyl-1H-indol-5-yl)-2-propenoate (6.50g) in a mixture ofacetic acid (14 ml) and tetrahydrofuran (15 ml) at 0° C., followed bythe dropwise addition of formaldehyde (1.75 ml of 40% aqueous solution).The mixture was stirred at room temperature for 3 hours and then dilutedwith ethyl acetate. 2N sodium hydroxide was addeddropwise with stirringuntil the pH of the aqueous layer was ca.9. The mixture was filtered,and the residue was washed with water followed by ethyl acetate and thendried to give the title compound (6.58 g), m.p. 174°-177° C. Found:C,75.85; H,6.83; N,7.53. C₂₂ H₂₄ N₂ O₂ requires: C,75.83; H,6.94;N,8.04%.

PREPARATION 13 Benzyl (E)-3-3-(dimethylaminomethyl)-2-methyl-1H-indol-4-yl!-2-propenoate

Treatment of benzyl (E)-3-(2-methyl-1H-indol-4-yl)-2-propenoate (6.20 g)with dimethylamine (3.2 ml of 33% solution in methylated spirit), andformaldehyde (1.68 ml of 40% aqueous solution) in acetic acid (13 ml)and tetrahydrofuran (15 ml) according to the method of Preparation 12gave thetitle compound as a foam (7.45 g), Rf. 0.3(SS3).

δ(CDCl₃): 2.25(6H,s), 2.37(3H,s), 3.49(2H,s), 5.28(2H,s), 6.48(1H,d)7.07(1H,dd), 7.22-7.44(7H,m), 8.08(1H,s), 9.07(1H,d).

PREPARATION 14 Benzyl (E)-3-3-(1H-imidazol-1-ylmethyl)-2-methyl-1H-indol-5-yl!-2-propenoate

A mixture of benzyl (E)-3-(3-dimethylaminomethyl)-2-methyl-1H-indol-5-yl!-2-propenoate (7.65 g)and imidazole (1.64 g) in dry dioxan (50 ml) was heated under reflux for4 hours. The solution was cooled, filtered and evaporated. Theresiduewas chromatographed on silica gel using dichloromethane/methanol(19:1) as eluent. Evaporation of the product fractions and triturationof the residue with ether gave the title compound (4.85 g), m.p.120°-122° C. Found: C,74.43; H,5.70; N,11.25. C₂₃ H₂₁ N₃ O₂ requires:C,74.37; H,5.70; N,11.32%.

PREPARATION 15 Benzyl (E)-3-3-(1H-imidazol-1-ylmethyl)-2-methyl-1H-indol-4-yl!-2-propenoate

A mixture of benzyl (E)-3-(3-dimethylaminomethyl)-2-methyl-1H-indol-4-yl!-2-propenoate (7.45 g),and imidazole (1.57 g) in xylene (50 ml) was heated under reflux for6hours and the solution was evaporated. The residue was chromatographedon silica gel using dichloromethane/methanol as eluent. Evaporation ofthe product fractions and trituration of the residue with ether gave thetitlecompound (3.85 g), m.p. 207°-208.5° C. Found: C,74.48; H,5.64;N,11.31. C₂₃ H₂₁ N₃ O₂ requires: C,74.37; H,5.70; N,11.32%.

PREPARATION 16 Methyl 5-nitro-3-(3-pyridylmethyl)-1H-indole-1-propanoate

Benzyltrimethylammonium hydroxide (0.8 ml of 40% solution in methanol)was added to a stirred mixture of 5-nitro-3-(3-pyridylmethyl)-1H-indole(7.34 g) and methyl acrylate (3.0 g) in dioxan (140 ml) and theresulting solution was stirred for 75 minutes and then evaporated. Theresidue was partitioned between water and ethyl acetate. The aqueouslayer was separated and extracted with ethyl acetate. The organic layerswere combined, washed with water and dried (Na₂ SO₄). Evaporation of thesolvent gave a solid which was crystallised from ethyl acetate/hexane togive the title compound (7.33 g), m.p. 101°-102° C. Found: C,63.85;H,4.86; N,12.37. C₁₈ H₁₇ N₃ O₄ requires: C,63.71; H,5.05; N,12.38%.

The following compounds were prepared similarly.

    __________________________________________________________________________     ##STR27##                                                                                          m.p.                                                    R.sup.1                                                                             R.sup.2                                                                          Y            °C.                                                                         Analytical Data                                    __________________________________________________________________________    1-imidazolyl                                                                        H  5-Nitro      152-154                                                                            Found: C, 58.88; H, 5.01; N, 17.07;                                           C.sub.16 H.sub.16 N.sub.4 O.sub.4 requires: C,                                58.53;                                                                        H, 4.91; N, 17.07%.                                1-imidazolyl                                                                        CH.sub.3                                                                         5-Nitro      150-151                                                                            Found: C, 59.82; H, 5.28; N, 16.41;                                           C.sub.17 H.sub.18 N.sub.4 O.sub.4 requires: C,                                59.64;                                                                        H, 5.30; N, 16.37%.                                1-imidazolyl                                                                        CH.sub.3                                                                         5-(E)-PhCH.sub.2 O.sub.2 CCHCH                                                             113-116                                                                            Found: C, 70.97; H, 5.95; N, 9.12;                                            C.sub.12 H.sub.27 N.sub.3 O.sub.4 requires: C,                                70.88;                                                                        H, 5.95; N, 9.19%.                                 1-imidazolyl                                                                        CH.sub.3                                                                         4-(E)-PhCH.sub.2 O.sub.2 CCHCH                                                             --   Found: C, 70.88; H, 5.90; N, 8.91;                                            C.sub.27 H.sub.27 N.sub.3 O.sub.4 requires: C,                                70.88;                                                                        H, 5.95; N, 9.19%.                                 3-pyridyl                                                                           H  5-(E)-t-BuO.sub.2 CCHCH                                                                    --   Found: C, 71.04; H, 6.67; N, 6.43;                                            C.sub.25 H.sub.28 N.sub.2 O.sub.4 requires: C,                                71.40;                                                                        H, 6.71; N, 6.66%.                                 3-pyridyl                                                                           H  4-(E)-t-BuO.sub.2 CCHCH                                                                     86-88                                                                             Found: C, 71.69; H, 6.59; N, 6.77;                                            C.sub.25 H.sub.28 N.sub.2 O.sub.4 requires: C,                                71.40;                                                                        H, 6.71; N, 6.66%.                                 3-pyridyl                                                                           CH.sub.3                                                                         5-(E)-t-BuO.sub.2 CCHCH                                                                     91-93                                                                             Found: C, 72.17; H, 6.96; N, 6.42;                                            C.sub.26 H.sub.30 N.sub.2 O.sub.4 requires: C,                                71.86;                                                                        H, 6.96; N, 6.45%.                                 3-pyridyl                                                                           CH.sub.3                                                                         4-(E)-t-BuO.sub.2 CCHCH                                                                    --   Found: C, 74.34; H, 6.07; N, 6.05;                                            C.sub.29 H.sub.28 N.sub.2 O.sub.4 requires: C,                                74.37;                                                                        H, 6.03; N, 5.98%.                                 __________________________________________________________________________

PREPARATION 17 Ethyl 5-nitro-3-(3-pyridyl)-1H-indole-1-butanoate

5-Nitro-3-(3-pyridyl)-1H-indole (0.60 g) was added portionwise to astirredsuspension of sodium hydride (0.11 g of 60% dispersion in mineraloil) in dry N,N-dimethylformamide (10 ml) at room temperature, and themixture wasstirred for 30 minutes. Ethyl 4-bromobutanoate (0.40 g) wasadded and the mixture was stirred for 18 hours. Further sodium hydride(0.11 g of 60% dispersion) was added, the mixture was stirred for 30minutes and then further ethyl 4-bromobutanoate (0.40 g) was added.Stirring was continued for an additional 4 hours and then the mixturewas partitioned between ethyl acetate and water. The organic layer wasseparated, washed twice with water and dried (MgSO₄). The solvent wasevaporated and the residue was chromatographed usingdichloromethane/methanol (100:1) as eluent. The product fractions werecombined and evaporated, and the residue was triturated with ether togive the title compound (0.51 g), m.p. 76°-78° C. Found: C,64.92;H,5.48; N,11.95. C₁₉ H₁₉ N₃ O₄ requires: C,64.58; H,5.42; N,11.89%.

PREPARATION 18 Methyl 5-nitro-3-(3-pyridyl)-1H-indole-1-propanoate

Benzyltrimethylammonium hydroxide (0.17 ml of 40% solution in methanol)wasadded to a stirred suspension of 5-nitro-3-(3-pyridyl)-1H-indole(0.95 g) and methyl acrylate (0.41 g) in a mixture of tetrahydrofuran(10 ml) and dioxan (15 ml), and the mixture was stirred at roomtemperature for 2 hours. Methanol (10 ml) was added to give a clearsolution followed by further methyl acrylate (0.41 g) andbenzyltrimethylammonium hydroxide solution (0.17 ml) and stirring wascontinued for an additional 18 hours. Potassium t-butoxide (100 mg) wasadded and stirring was continued for a further 6 hours and the solutionwas evaporated. The residue was partitioned between ethyl acetate andwater and the organic layer was separated and dried (MgSO,). Evaporationof the solvent gave a solid whichwas crystallised fromdichloromethane/hexane to give the title compound (0.48 g), m.p.123°-125° C. Found: C,62.85H,4.62; N,12.91. C₁₇ H₁₅ N₃ O₄ requires:C,62.76; H,4.65; N,12.92%.

PREPARATION 19 Methyl3-(4-fluorophenylmethyl)-5-nitro-1H-indole-1-propanoate

Tetrabutylammonium bromide (0.262 g) and potassium t-butoxide (100 mg)wereadded to a stirred solution of3-(4-fluorophenylmethyl)-5-nitro-1H-indole (2.20 g) and methyl acrylate(0.84 g) in dioxan (30 ml) and the solution was stirred at roomtemperature for 66 hours. Further quantities of methylacrylate (0.5 g),tetrabutylammonium bromide (262 mg) and potassium t-butoxide (100 mg)were added and stirring was continued for an additional 5 hours. Thesolution was poured into water and the mixture wasextracted twice withether. The combined ether extracts were washed with water, dried (Na₂SO₄) and evaporated. The residue was chromatographed on silica gel usinghexane/dichloromethane (1:4) as eluent. The product fractions werecombined and evaporated to give the title compound as a gum (1.90 g).Found: C,64.43; H,4.39; N,7.65. C₁₉H₁₇ FN₂ O₄ requires: C,64.03; H,4.81;N,7.86%.

PREPARATION 20 Methyl 5-nitro-1H-indole-1-propanoate

Reaction of 5-nitro indole (3.0 g) with methyl acrylate (2.29 g) in thepresence of potassium t-butoxide (0.258 g) and tetrabutylammoniumbromide according to the method of Preparation 19 gave the titlecompound (3.0 g),m.p. 97°-99° C. Found: C,57.86; H,4.84; N,10.78. C₁₂H₁₂ N₂ O₄ requires: C,58.06; H,4.87; N,11.28%.

PREPARATION 21 Methyl5-(2-carboxyethyl)-3-(1H-imidazol-1-ylmethyl)-2-methyl-1H-indole-1-propanoate

A solution of benzyl (E)-3-3-(1H-imidazol-1-ylmethyl)-1-(2-methoxycarbonylethyl)-2-methyl-1H-indol-5-yl!-2-propenoate(2.0 g) in tetrahydrofuran (40 ml) was hydrogenatedat room temperatureand 4.5 atm. in the presence of 10% palladium on carbon(0.20 g) untilreaction was complete (5 hours). The mixture was filtered and theresidue was washed with ethyl acetate. The combined filtrate andwashings were evaporated and the residue was triturated with ether togivethe title compound (1.52 g), m.p. 134°-137° C. Found: C,65.31;H,6.35; N,10.70. C₂₀ H₂₃ N₃ O₄ requires: C,65.02; H,6.28N,11.38%.

PREPARATION 22 Methyl4-(2-carboxyethyl)-3-(1H-imidazol-1-ylmethyl)-2-methyl-1H-indole-1-propanoate

Hydrogenation of benzyl (E)-3-3-(1H-imidazol-1-ylmethyl)-1-(2-methoxycarbonylethyl)-2-methyl-1H-indol-4-yl!-2-propenoate(1.40 g) in the presence of 10% palladium on carbon(0.15 g) according tothe method of Preparation 21 gave the title compound (0.82 g), m.p.136°-138° C.

δ(DMSOd₆): 2.34(2H,t), 2.57(3H,s), 2.74(2H,t), 2.96(2H,t), 3.54(3H,s),4.40(2H,t), 5.32(2H,s), 6.78(1H,d), 6.82(1H,s), 6.90(1H,s), 6.98(1H,dd),7.29(1H,d), 7.43(1H,s).

PREPARATION 23 t-Butyl1-(2-methoxycarbonylethyl)-3-(3-pyridylmethyl)-1H-indole-5propanoate

A mixture of t-butyl (E)-3-1-(2-methoxycarbonylethyl)-3-(3-pyridylmethyl)-1H-indol-5-yl!-2-propenoate(7.86 g), 10% palladium on carbon (0.70 g) and ammonium formate (5.60 g)in a mixture of methanol (40 ml) and tetrahydrofuran (40 ml) was heatedat 60° C. for 3 hours and then cooled. The mixture was filtered and theresidue was washed with methanol. The filtrate and washings werecombined and evaporated, and the residue-was partitioned between waterand ether. The organic layer was separated and the aqueous layer wasextracted with ether. The organic layers were combined, washed withwater and dried (MgSO₄). Evaporation of the solvent gave the titlecompound as an oil (7.80 g). Found: C,70.51; H,6.98; N,6.54. C₂₅ H₃₀ N₂O₄ requires: C,71.06; H,7.16; N,6.63%.

PREPARATION 24 t-Butyl1-(2-methoxycarbonylethyl)-3-(3-pyridylmethyl)-1H-indole-4-propanoate

Treatment of t-butyl (E)-3-1-(2-methoxycarbonylethyl)-3-(3-pyridylmethyl)-1H-indole-4-yl!-2-propenoate(5.15 g) with 10% palladium on carbon (0.50 g) and ammonium formate(7.71 g) according to the method of Preparation 23 gave the titlecompound, (4.67 g) m.p. 80°-82° C. Found: C,71.43; H,7.06; N,6.35. C₂₅H₃₀ N₂ O₄ requires: C,71.06; H,7.16; N,6.63%.

PREPARATION 25 Methyl5-(2-carboxyethyl)-3-(3-pyridylmethyl)-1H-indole-1-propanoate

Trifluoroacetic acid (15 ml) was added to a stirred solution of t-butyl1-(2-methoxycarbonylethyl)-3-(3-pyridylmethyl)-1H-indole-5-propanoate(7.60 g) in dry dichloromethane (100 ml) at room temperature, andstirringwas continued for 18 hours. The solution was evaporated and theresidue wasazeotroped with toluene and then dissolved in ethyl acetate.Saturated sodium bicarbonate solution was added slowly with shakinguntil the pH of the aqueous layer was 4-5. The organic layer was thenseparated, washed with water and dried (MgSO₄). The solvent wasevaporated and the residue was triturated with ether to give the titlecompound (5.70 g), m.p. 108°-110° C. Found: C,68.80; H,6.16; N,7.57%.C₂₁ H₂₂ N₂ O₄ requires: C,68.83; H,6.05; N,7.65%.

The following compounds were prepared similarly from the correspondingt-butyl ester.

    __________________________________________________________________________    Structure                   m.p. °C.                                                                    Analytical Data                              __________________________________________________________________________     ##STR28##                  199-201                                                                            Found: C, 68.65; H, 6.27; N, 7.53.                                            C.sub.21 H.sub.22 N.sub.2 O.sub.4                                             requires: C, 68.83; H, 6.05; N, 7.65%.        ##STR29##                  180-182                                                                            Found: C, 69.65; H, 5.73; N, 7.19.                                            C.sub.22 H.sub.22 N.sub.2 O.sub.4                                             requires: C, 67.82; H, 5.86; N,              __________________________________________________________________________                                     7.40%.                                   

PREPARATION 26 Methyl5-(2-carboxyethyl)-2-methyl-3-(3-pyridylmethyl)-1H-indole-1-propanoate

A mixture of (E)-3-1-(2-methoxycarbonylethyl)-2-methyl-3-(3-pyridylmethyl)-1H-indol-5-yl!-2-propenoicacid (2.02 g), 10% palladium on carbon (0.20 g) and ammonium formate(1.68 g) in methanol (20 ml) and tetrahydrofuran (20 ml) was heated at60° C. for 4 hours and then cooled and filtered. The residue was washedwith methanol, and the filtrate and washings were combined andevaporated. The residue was triturated with dilute acetic acid to give agummy solid. The solid was filtered off and boiled with ether to givethe title compound as a crystalline solid (1.79 g), m.p. 144°-146° C.Found: C,69.60; H,6.20; N,7.16. C₂₂ H₂₄ N₂ O₄ requires: C,69.45; H,6.36;N,7.37%.

PREPARATION 27 Methyl4-(2-carboxyethyl)-2-methyl-3-(3-pyridylmethyl)-1H-indole-1-propanoate

Treatment of benzyl1-(2-methoxycarbonylethyl)-2-methyl-3-(3-pyridylmethyl)-1H-indole-1-propanoate(6.45 g) with palladium on carbon (0.65 g) and ammonium formate (8.90 g)according to the method of Preparation 26 gave the title compound(3.76g). m.p. 165°-167° C. Found: C,69.43; H,6.42; N,7.37. C₂₂ H₂₄ N₂ O₄requires: C,69.45; H,6.36; N,7.37%.

PREPARATION 28 Methyl5-(2-benzyloxycarbonylaminoethyl)-3-(1H-imidazol-1-ylmethyl)-2-methyl-1H-indole-1-propanoate

Diphenylphosphoryl azide (0.744 g) was added to a mixture of methyl5-(2-carboxyethyl)-3-(1H-imidazol-1-ylmethyl)-2-methyl-1H-indole-1-propanoate(1.0 g) and triethylamine (0.274 g) in dry dioxan (5 ml) at 50° C. Thesolution was then heated at 100° C. for 1 hour to give a clear solution.Benzyl alcohol (0.352 g) was added and the solution was heated at 1000°C. for a further 20 hours and then evaporated. The residue waspartitioned between ethyl acetate and sodium bicarbonate solution. Theorganic layer was separated, washed with brine and dried (MgSO₄). Thesolvent was evaporated and the residue was chromatographed on silica gelusing dichloromethane/methanol (97:3) as eluent. The product fractionswere combined and evaporated to give the title compound as a gum (0.41g). Found: C,68.12; H,6.41; N,11.23. C₂₇ H₃₀ N₄ O₄ requires: C,68.33;H,6.37; N,11.81%.

The following compounds were prepared similarly using either benzylalcoholor t-butanol.

    __________________________________________________________________________    Structure                         m.p. °C.                                                                    Analytical Data                        __________________________________________________________________________     ##STR30##                        Gum  Rf. 0.4(SS4). δ(CDCl.sub.3):                                            1.46(9H, s), 2.82(2H, t), 2.89(2H,                                            t), 3.42(2H, m), 3.67(3H, s),                                                 4.08(2H, s), 4.41(2H, t), 4.58(1H,                                            br), 6.84(1H, s), 7.08(1H, d),                                                7.22(1H, m), 7.28- 7.32(2H, m),                                               7.55(1H, d), 8.47(1H, d), 8.59(1H,                                            s).                                     ##STR31##                        Gum  Rf. 0.5(SS3). δ(CDCl.sub.3):                                            1.44(9H, s), 2.80(2H, t), 2.99(2H,                                            t), 3.32(2H, m), 2.65(3H, s),                                                 4.15(2H, s), 4.38(2H, t), 4.57(1H,                                            br), 6.75(1H, s), 6.87(1H, d),                                                7.16-7.22(3H, m), 7.45(1H, d),                                                8.44(1H, d), 8.50(1H, s).               ##STR32##                        127.5- 129.5                                                                       Found: C, 68.15; H, 6.42; N,                                                  11.77. C.sub.27 H.sub.30 N.sub.4                                              O.sub.4 requires: C, 68.33; H,                                                6.37; N, 11.81%.                       __________________________________________________________________________

PREPARATION 29 Methyl5-(2-t-butoxycarbonylaminoethyl)-2-methyl-3-(3-pyridylmethyl)-1H-indole-1-propanoate

Diphenylphosphoryl azide (3.99 g) was added to a stirred mixture ofmethyl5-(2-carboxyethyl)-2-methyl-3-(3-pyridylmethyl)-1H-indole-1-propanoate(5.00 g) and triethylamine (1.46 g) in dry t-butanol (30 ml) and themixture was heated at 100° C. for 18 hours and then evaporated.Theresidue was dissolved in dichloromethane, and the solution was washedtwicewith water and dried (MgSO₄). The solvent was evaporated and theresidue was chromatographed on silica gel. Elution with dichloromethaneand evaporation of the product fractions gave the title compound as agum (4.51 g), Rf. 0.35(SS4). δ(CDCl₃): 1.42(9H,s), 2.37(3H,s),2.73(2H,t), 2.82(2H,t), 3.36(2H,m), 3.68(3H,s), 4.05(2H,s), 4.39(2H,t),4.50(1H,br), 7.00(1H,d), 7.10-7.25(3H,m) 7.41 (1H,d), 8.39(1H,d),8.50(1H,s).

PREPARATION 30 Methyl4-(2-t-butoxycarbonylaminoethyl)-2-methyl-3-(3-pyridylmethyl)-1H-indole-1-propanoate

Treatment of methyl4-(2-carboxyethyl)-2-methyl-3-(3-pyridylmethyl)-1H-indole-1-propanoate(3.70 g) with diphenylphosphoryl azide (2.95 g), triethylamine (1.08 g),and t-butanol (30 ml) as described in Preparation 29 gave the titlecompound as an oil (3.46 g), Rf. 0.5 (SS2). δ(CDCl₃): 1.44(9H,s),2.37(3H,s), 2.77(2H,t), 2.87(2H,t), 3.23(2H,m), 3.68(3H,s), 4.28(2H,s),4.45(2H,t), 4.53(1H,br), 6.82(1H,d), 7.10-7.13(2H,m), 7.21(1H,d),7.29(1H,d), 8.38-8.42(2H,m).

PREPARATION 31 Methyl 5-amino-3-(3-pyridylmethyl)-1H-indole-1-propanoate

A mixture of methyl 5-nitro-3-(3-pyridylmethyl)-1H-indole-1-propanoate(1.20 g) and 10% palladium on carbon (120 mg) in methanol (75 ml) washydrogenated at 50° C. and 4.5 atm. until reduction was complete(2hours). The mixture was filtered and the catalyst was washed well withmethanol. The filtrate and washings were combined and evaporated to givethe title compound as an oil (1.05 g), Rf. 0.2(SS2). δ(CDCl₃):2.76(2H,t), 3.45(2H,br), 3.63(3H,s), 3.98(2H,s), 4.32(2H,t),6.66-6.68(1H,dd), 6.72(1H,d), 6.77(1H,s), 7.11(1H,d), 7.14-7.18(1H,m),7.48-7.51(1H,m), 8.42-8.44(1H,m), 8.56(1H,d).

The following compounds were prepared similarly as oils.

    __________________________________________________________________________     ##STR33##                                                                    R.sup.1                                                                              X  R.sup.2                                                                          m R.sup.7                                                                          Analytical Data                                             __________________________________________________________________________    1-imidazolyl                                                                         CH.sub.2                                                                         H  2 CH.sub.3                                                                         Rf. 0.7(SS5).                                                                 δ(CDCl.sub.3): 2.83(2H, t), 3.47(2H, br),                               3.67(3H, s)                                                                   4.38(2H, t), 5.19(2H, s), 6.68(1H, d), 6.71-6.74(1H,                          dd),                                                                          6.96(1H, s), 7.06(1H+1H, s), 7.15(1H, d), 7.59(1H, s).      1-imidazolyl                                                                         CH.sub.2                                                                         CH.sub.3                                                                         2 CH.sub.3                                                                         Rf. 0.4(SS2).                                                                 δ(CDCl.sub.3): 2.42(3H, s), 2.77(2H, t), 3.50(2H,                       br),                                                                          3.68(3H, s), 4.39(2H, t), 5.16(2H, s), 6.63-6.69(2H,                          m),                                                                           6.93(1H, s), 7.05(1H, s), 7.14(1H, d), 7.54(1H, s).         4-fluorophenyl                                                                       CH.sub.2                                                                         H  2 CH.sub.3                                                                         Rf. 0.4(SS6).                                                                 δ(CDCl.sub.3): 2.77(2H, t), 3.42(2H, br),                               3.65(1H, s),                                                                  3.97(1H, s), 4.33(2H, t), 6.67(1H, dd), 6.68-                                 6.69(2H, d+s), 6.95(2H, t), 7.12(1H, d), 7.17-                                7.22(2H, m).                                                3-pyridyl                                                                            direct                                                                           H  2 CH.sub.3                                                                         Rf. 0.2(SS2).                                                      link       δ(CDCl.sub.3): 2.85(2H, t), 3.65(2H, br),                               3.67(3H, s),                                                                  4.44(2H, t), 6.75(1H, dd), 7.18(1H, d), 7.27(1H, s),                          7.27(1H, d), 7.30-7.34(1H, m), 7.87(1H, m),                                   8.47(1H, dd), 8.86(d).                                      3-pyridyl                                                                            direct                                                                           H  3 C.sub.2 H.sub.5                                                                  Rf. 0.2(SS2).                                                      link       δ(CDCl.sub.3): 1.24(3H, t), 2.15(2H, m), 2.32(2H,                       t),                                                                           3.45(2H, br), 4.11(2H, t), 4.19(2H, t), 7.18-7.23(3H,                         m),                                                                           7.30-7.35(1H, m), 7.89(1H, m), 8.47(1H, dd),                                  8.86(1H, dd).                                               H      direct                                                                           H  2 CH.sub.3                                                                         Rf. 0.25(SS6).                                                     link       δ(CDCl.sub.3): 2.80(2H, t), 3.35(2H, br),                               3.67(2H, s),                                                                  4.39(2H, t), 6.30(1H, d), 6.68(1H, dd), 6.93(1H, d),                          7.04(1H, d), 7.14(1H, d).                                   __________________________________________________________________________

PREPARATION 32 Methyl5-(2-aminoethyl)-3-(1H-imidazol-1-ylmethyl)-2-methyl-1H-indole-1-propanoat

A solution of methyl5-(2-benzyloxycarbonylaminoethyl)-3-(1H-imidazol-1-ylmethyl)-2-methyl-1H-indole-1-propanoate(0.57 g) in tetrahydrofuran (50 ml) was hydrogenated at room temperatureand 4.5 atm. pressure in the presence 10% palladium on carbon (50 mg)for 20 hours. The mixture was filtered and the residue was washed withmethanol. The filtrate and washings were combined and evaporated to givea gum which was chromatographed on silica gel. Elution withdichloromethane/methanol (19:1) gave impurity, and then further elutionwith dichloromethane/methanol/0.880 ammonia solution (95:5:1) gavepureproduct. The product fractions were evaporated to give the titlecompound as a gum (0.325 g), Rf. 0.4 (SS3). The product was useddirectly for further reaction.

PREPARATION 33 Methyl4-(2-aminoethyl)-3-(1H-imidazol-1-ylmethyl)-2-methyl-1H-indole-1-propanoate

Hydrogenation of methyl4-(2-benzyloxycarbonylaminoethyl)-3-(1H-imidazol-1-ylmethyl)-2-methyl-1H-indole-1-propanoate(0.50 g) in tetrahydrofuran (20 ml) in the presence of 10% palladium oncarbon (100 mg+a further 50 mg quantities after 24 and 48hours) for 72hours, followed by work up as described for Preparation 32 gave thetitle compound as a gum (0.20 g), Rf. 0.15(SS3). δ(CDCl₃): 1.70(2H,br),2.47(3H,s), 2.81(2H,t), 2.88(4H,s), 3.70(3H,s), 4.48(2H,t), 5.37(2H,s),6.86(1H,s), 6.95(1H,d), 7.04(1H,s), 7.17(1H,m), 7.24(1H,d), 7.42(1H,s).

PREPARATION 34 Methyl5-(2-aminoethyl)-3-(3-pyridylmethyl)-1H-indole-1-propanoate

Trifluoroacetic acid (5 ml) was added to a stirred solution of methyl5-(2-t-butoxycarbonylaminoethyl)-3-(3-pyridylmethyl)-1H-indole-1-propanoate (5.0 g) in dry dichloromethane (50 ml) and the solutionwas stirred for 3 hours. An additional 5 ml of trifluoroacetic acid wasthen added and stirring was continued for a further 2 hours. Thesolution was evaporated and the residue was partitioned betweendichloromethane and dilute aqueous ammonia. The aqueous layer wasseparated and extracted withdichloromethane. The organic layers werecombined and evaporated. Water (ca50 ml) was added followed bysufficient acetic acid to adjust the pH to ca4. The solution was washedtwice with ethyl acetate and then made basic with concentrated aqueousammonia solution. The mixture was extracted twice with dichloromethaneand the combined extracts were dried (MgSO₄) and evaporated to give thetitle compound as a gum (2.51 g), Rf. 0.15(SS3).

(CDCl₃): 1.39(2H,s), 2.80-2.86(4H,m), 2.98(2H,t), 3.67(3H,s),4.08(2H,s), 4.42(2H,t), 6.83(1H,s), 7.08(1H,d), 7.20(1H,m),7.27-7.29(2H,m), 7.54(1H,d), 8.45(1H,d), 8.59(1H,s).

The following compounds were prepared similarly.

    __________________________________________________________________________    Structure                  Analytical Data                                    __________________________________________________________________________     ##STR34##                 Rf. 0.4(SS5). δ(CDCl.sub.3): 1.47(2H,                                   s), 2.38(3H, s), 2.71-2.80(4H, m), 2.92(2H,                                   t), 3.66(3H, s), 4.04(2H, s), 4.40(2H, t),                                    7.00(1H, d), 7.11(1H, m), 7.18(1H, s),                                        7.22(1H, d), 7.40(1H, d), 8.36(1H, d),                                        8.52(1H, s).                                        ##STR35##                 Rf. 0.45(SS3). δ(CDCl.sub.3): 1.08(2H,                                  br), 2.77(2H, t), 2.88-2.97(4H, m), 3.65(3H,                                  s), 4.22(2H, s), 4.35(2H, t), 6.69(1H, s),                                    6.87(1H, d), 7.12-7.26(3H, m), 7.45(1H, d),                                   8.45(1H, d), 8.51(1H, s).                           ##STR36##                 Rf. 0.4(SS3). δ(CDCl.sub.3): 2.37(3H,                                   s), 2.76(2H, t), 2.85(2H, t), 2.97(2H, t),                                    3.68(3H, s), 4.21(2H, s), 4.30(2H, br),                                       4.44(2H, t), 6.82(1H, d), 7.05-7.11(2H, m),                                   7.20(1H, d), 7.24-7.26(1H, m), 8.31(1H, d),                                   8.45(1H, s).                                       __________________________________________________________________________

We claim:
 1. A compound of formula (I): ##STR37## or a pharmaceuticallyacceptable salt or biolabile ester thereof, wherein R¹ is C₁ -C₄ alkyl,phenyl optionally substituted by up to three substituents independentlyselected from C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halogen and CF₃, or is1-imidazolyl, 3-pyridyl or 4-pyridyl;R² is H or C₁ -C₄ alkyl, R³ is SO₂R₄ or COR⁴ where R⁴ is C₁ -C₄ alkyl, C₁ -C₃ perfluoroalkyl(CH₂)_(p), C₃-C₆ cycloalkyl(CH₂)_(p), aryl(CH₂)_(p), furyl(CH₂)_(p), thienyl(CH₂)_(p)or pyridyl(CH₂)_(p), p being 0, 1 or 2, or R⁴ may be NR⁵ R⁸ where R⁵ isH or C₁ -C₄ alkyl and R⁶ is C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl or aryl; Xis CH₂ or a direct link, with the proviso that when R¹ is 1-imidazolylthen X is CH₂ ; m is 2, or 3; n is 0, 1 or 2, and wherein the group(CH₂)_(n) NHR³ is attached at the 5-position when n is 0 or 1, or at the5- or 4-position when n is
 2. 2. A compound, pharmaceutically acceptablesalt or biolabile ester, according to claim 1, where R¹ is optionallysubstituted phenyl or pyridyl, R² is H, R³ is SO₂ R⁴ where R⁴ isoptionally substituted phenyl, X is CH₂, m is 2, n is 0 or 2, and(CH₂)_(n) NHR³ is attached at the 5-position.
 3. A compound,pharmaceutically acceptable salt or biolabile ester, according to claim1, where R¹ is pyridyl, R² is H, R³ is SO₂ R⁴ where R⁴ is optionallysubstituted phenyl or, R³ is COR⁴ where R⁴ is alkyl, X is CH₂, m is 2, nis 2 and (CH₂)_(n) NHR³ is attached at the 4-position.
 4. A compound,pharmaceutically acceptable salt or biolabile ester, according to claim1, where R¹ is 4-fluorophenyl, R³ is arylsulphonyl, X is CH₂, m is 2, nis 0 and (CH₂)_(n) NHR³ is attached at the 5-position, or wherein R¹ ispyridyl, R³ is 3-methylbutanoyl, X is CH₂, m is 2, n is 2 and (CH₂)_(n)NHR³ is attached at the 4-position.
 5. Any one of the followingcompounds, or pharmaceutically acceptable salts thereof, according toclaim 1:(i) methyl 5-2-(4-fluorophenylsulphonyl)amino)ethyl!-3-(3-pyridylmethyl)-1H-indole-1-propanoate;(ii) methyl5-((4-fluorophenylsulphonyl)amino)-3-(1H-imidazol-1-ylmethyl)1H-indole-1-propanoate;(iii) methyl5-((4-fluorophenylsulphonyl)amino)-3-(1H-imidazol-1-ylmethyl)-2-methyl-1H-indole-1-propanoate;(iv) methyl5-((4-fluorophenylsulphonyl)amino)-3-(4-fluorophenylmethyl)-1H-indole-1-propanoate;(v) methyl 5-((4-chlorophenylsulphonyl)amino)-3-(4-fluorophenylmethyl)-1H-indole-1-propanoate; (vi) methyl5-((4-chlorophenylsulphonyl)amino)-3-(3-pyridyl)-1H-indole-1--propanoate;(vii) ethyl5-((4-chlorophenylsulphonyl)amino)-3-(3-pyridyl)-1H-indole-1-butanoate;(viii) methyl5-((4-fluorophenylsulphonyl)amino)-3-(3-pyridylmethyl)-1H-indole-1-propanoate;(ix) methyl5-((4-fluorophenylsulphonyl)amino)-3-(3-pyridylmethyl)-1H-indole-1-butanoate;(x) methyl 5-2-((4-fluorophenylsulphonyl)amino)ethyl!-3-(1H-imidazol-1-ylmethyl)-2-methyl-1H-indole-propanoate;(xi) methyl 4-2-((4-fluorophenylsulphonyl)amino)ethyl!-3-(1H-imidazol-1-ylmethyl)-2-methyl-1H-indole-propanoate;(xii) methyl 5-2-((4-fluorophenylsulphonyl)amino)ethyl!-3-(3-pyridylmethyl)-1H-indole-propanoate;(xiii) methyl 5-2-(dimethylaminosulphonyl)amino)ethyl!-3-(3-pyridylmethyl)-1H-indole-propanoate;(xiv) methyl 5-2-(3-methylbutanoylamino)ethyl!-3-(3-pyridylmethyl)-1H-indole-propanoate;(xv) methyl 4-2-((4-fluorophenylsulphonyl)amino)ethyl!-3-(3-pyridylmethyl)-1H-indole-propanoate;(xvi) methyl 4-2-((dimethylaminosulphonyl)amino)ethyl!-(3-pyridylmethyl)-1H-indole-propanoate;(xvii) methyl 4-2-((3-methylbutanoyl)amino)ethyl!-3-(3-pyridylmethyl)-1-H-indole-propanoate;(xviii) methyl 5-2-((4-fluorophenylsulphonyl)amino)ethyl!-3-(3-pyridylmethyl))-2-methyl-1H-indole-propanoate;(xix) methyl 5-2-((4-iodophenylsulphonyl)amino)ethyl!-3-(3-pyridylmethyl)2-methyl-1H-indole-propanoate;(xx) methyl 5-2-((4-trifluoromethylphenylsulphonyl)amino)-3-(3pyridylmethyl)-2-methyl-1H-indole-propanoate;(xxi) methyl 4-2-((4-fluorophenylsulphonyl)amino)ethyl!-3-(3-pyridylmethyl)2-methyl-1H-indole-propanoate;(xxii) methyl 5- 4-chlorophenylsulphonyl)amino!-1H-indole-propanoate;(xxiii) methyl 5- 4-fluorophenylsulphonyl)amino!-1H-indole-propanoate;(xxiv) methyl 5- (phenylsulphonyl)amino!-3-(4-fluorophenyl)methyl!-1H-indole-propanoate (xxv) methyl 3-(4-fluorophenyl)methyl!-5-(4-trifuoromethylphenylsulphonyl)amino!-1H-indole-propanoate; (xxvi)methyl 3- (4-fluorophenyl)methyl!-5-(4-methoxyphenylsulphonyl)amino!-1H-indole-propanoate; (xxvii) methyl 3-(4-fluorophenyl)methyl!-5- (4-methylphenysulphonyl)amino!-1-H-indolepropanoate. (xxviii) methyl 5-(2-cyclopropyl)acetyl!amino!ethyl-3-(3-pyridylmethyl))1H-indole-1-propanoate;(xxix) 5-(4-Fluorophenyl)sulphonyl!amino-3-(3-pyridylmethyl)-1H-indole-1-propanoicacid; (xxx) 5-(4-fluorophenylsulphonyl)amino!-3-(1H-imidazol-1-ylmethyl)-1H-indole-1-propanoicacid; (xxxi) 5-(4-fluorophenylsulphonyl)amino!-3-(1H-imidazol-1-ylmethyl)-2-methyl-1H-indole-1-propanoicacid; (xxxii) 5-(4-fluorophenylsulphonyl)amino!-3-(4-fluorophenylmethyl)-1H-indole-1-propanoicacid; (xxxiii) 5-(4-chlorophenylsulphonyl)amino!-3-(4-fluorophenylmethyl)-1H-indole-1-propanoicacid; (xxxiv)5-((4-chlorophenylsulphonyl)amino!-3-(3-pyridyl)-1H-indole-1-propanoicacid; (xxxv) 5-(4-chlorophenylsulphonyl)amino!-3-(3-pyridyl)-1H-indole-1-butanoic acid;(xxxvi) 5-(4-fluorophenylsulphonyl)amino!-3-(3-pyridylmethyl)-1H-indole-1-butanoicacid; (xxxvii) 5-2-((4-fluorophenylsulphonyl)amino)ethyl!-3-(1H-imidazol-1-ylmethyl)-2-methyl-1H-indole-1-propanoicacid; (xxxviii) 4-2-((4-fluorophenylsulphonyl)amino)ethyl!-3-(1H-imidazol-1ylmethyl)-2-methyl-1H-indole-1-propanoicacid; (xxxix) 5-2-((4-fluorophenylsulphonyl)amino)ethyl!-3-(3-pyridylmethyl)-1H-indole-1-propanoicacid; (xI) 5-2-((methylsulphonyl)amino)ethyl!-3-(3-pyridylmethyl)-1H-indole-1-propanoicacid; (xIi) 5-2-((dimethylaminosulphonyl)amino)!-3-(3-pyridylmethyl)-1H-indole-1-propanoicacid; (xiii) 5-2-((3-methylbutanoyl)amino)ethyl!-3-(3-pyridylmethyl)-1H-indole-1-propanoicacid; (xIiii) 5-2-((cyclopropylacetyl)amino)ethyl!-3-(3-pyridylmethyl)-1H-indole-1-propanoicacid; (xIiv) 4-2-((4-fluorophenylsulphonyl)amino)ethyl!-3-(3-pyridylmethyl)-1H-indole-1-propanoicacid; (xIv) 5-2-((dimethylaminosulphonyl)amino)ethyl!-3-(3-pyridylmethyl)-1H-indole-1-propanoicacid; (xIvi) 5-2-((3-methylbutanoyl)amino)ethyl!-3-(3-pyridylmethyl)-1H-indole-1-propanoicacid; (xIvii) 5-2-((4-fluorophenylsulphonyl)amino)ethyl!-3-(3-pyridylmethyl)-2-methyl-1H-indole-1-propanoicacid; (xIviii) 5-2-((4-iodophenylsulphonyl)amino)ethyl!-3-(3-pyridylmethyl)-2-methyl-1H-indole-1-propanoicacid; (iI) 5-2-((4-trifiuoromethylphenylsulphonyl)amino)ethyl!-3-(3pyridylmethyl)-2-methyl-1H-indole-1-propanoicacid; (I) 4-2-((4-fluorophenylsulphonyl)amino)ethyl!-3-(3-pyridylmethyl)-2methyl-1H-indole-1-propanoicacid; (Ii) 5- (4-chlorophenylsulphonyl)amino!-1H-indole-1-propanoicacid; (Iii) 5- (4-fluorophenylsulphonyl)amino!-1H-indole-1-propanoicacid; (Iiii) 3-(4-fluorophenyl)methyl-5(phenylsulphonyl)amino!-1H-indole-1-propanoic acid; (Iiv)3-(4-fluorophenyl)methyl-5-(4-trifluoromethylphenylsulphonyl)amino!-1H-indole-1-propanoic acid;(Iv) 3-(4-fluorophenyl)methyl-5(4-methoxyphenylsulphonyl)amino!-1H-indole-1-propanoic acid; (Ivi)3-(4-fluorophenyl)methyl-5-(4-methylphenylsulphonyl)amino!-1H-indole-1-propanoic acid and; (Ivii)5- (4-fluorophenyl)sulphonyl!amino-2,3-dimethyl-1 H-indole-1propanoicacid.
 6. A compound, salt or ester according to claim 1, which isradiolabelled.
 7. A biolabile ester of a carboxylic acid compound of theformula (I) as claimed in claim 1, wherein said biolabile ester is alower alkyl ester having from one to four carbon atoms in the alkylmoiety (C₁ -C₄ alkyl).
 8. A pharmaceutical composition for treating orpreventing diseases or disorders mediated by selectively antagonizingthe effect of thromboxane A₂ or its precursor prostaglandin H₂ at thethromboxane receptor in a mammalian subject, comprising a compound ofthe formula (I), or a pharmaceutically acceptable salt or biolabileester thereof, as claimed according to claim 1, together with apharmaceutically acceptable diluent or carrier.
 9. The method oftreating or preventing disease or disorders mediated by selectivelyantagonizing the effect of thromboxane A₂ or its precursor prostaglandinH₂ at the thromboxane receptor in a mammalian subject, which comprisesadministering to said mammal a therapeutically-effective amount of acompound of the formula (I)), or a pharmaceutically acceptable salt orbiolabile ester thereof, as claimed in claim 1.